Prevention and treatment of variceal haemorrhage in 2017

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1 Received: 12 October 2016 Accepted: 19 October 2016 DOI: /liv REVIEW ARTICLE Prevention and treatment of variceal haemorrhage in 2017 Felix Brunner 1 Annalisa Berzigotti 1 Jaime Bosch 1,2 1 Swiss Liver Center, Hepatology, University Clinic for Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland 2 Hepatic Hemodynamic Laboratory, Hospital Clinic-IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain Funding Information None. Correspondence Prof. Jaime Bosch, MD, PhD, FRCP, Hepatic Hemodynamic Laboratory, Hospital Clinic, IDIBAPS and CIBEREHD, University of Barcelona, Barcelona, Spain. jbosch@clinic.ub.es Handling Editor: Francesco Negro Abstract Variceal haemorrhage is a major complication of portal hypertension that still causes high mortality in patients with cirrhosis. Improved knowledge of the pathophysiology of portal hypertension has recently led to a more comprehensive approach to prevent all the complications of this condition. Thus, optimal treatment of portal hypertension requires a strategy that takes into account the clinical stage of the disease and all the major variables that affect the risk of progression to the next stage and death. In patients with compensated liver disease, the correction of factors influencing the progression of fibrosis, in particular aetiologic factors, is now feasible in many cases and should be achieved to prevent the development or progression of gastroesophageal varices and hepatic decompensation. Once gastroesophageal varices have developed, non- selective beta- blockers remain the cornerstone of therapy. Carvedilol provides a greater decrease in portal pressure and is currently indicated as a first- choice therapy for primary prophylaxis. The treatment of acute variceal haemorrhage includes a combination of vasoactive drugs, antibiotics and endoscopic variceal band ligation. In highrisk patients, the early use of transjugular intrahepatic portosystemic shunt (TIPS) lowers the risk of re- bleeding and improves survival. Transjugular intrahepatic portosystemic shunt is the choice for uncontrolled variceal bleeding; a self- expandable metal stent or balloon tamponade can be used as a bridging measure. The combination of non- selective beta- blockers and endoscopic variceal band ligation reduces the risk of recurrent variceal bleeding and improves survival. In these cases, statins seem to further improve survival. Transjugular intrahepatic portosystemic shunt is indicated in patients who rebleed during secondary prophylaxis. KEYWORDS cirrhosis, portal hypertension, variceal bleeding, varices 1 INTRODUCTION Portal hypertension is the most severe and frequent complication of chronic liver disease. This complication is the cause of most of the severe clinical symptoms of cirrhosis, such as bleeding from gastroesophageal varices (GEVs) and portal hypertensive gastropathy, a scites, spontaneous bacterial peritonitis (SBP), hepatorenal syndrome (HRS), hepatic encephalopathy (HE), hepatopulmonary and porto- pulmonary syndrome, bacteremia and hypersplenism. Abbreviations: (c)acld, (compensated) advanced chronic liver disease; ACE, angiotensin-converting enzyme; BRTO, balloon-occluded retrograde transvenous obliteration; CSPH, clinically significant portal hypertension; CT, computer tomography; EIS, endoscopic injection sclerotherapy; e-nos, endothelial NO synthase; EV, oesophageal varices; EVL, endoscopic variceal band ligation; GEV, gastroesophageal varices; GOV1+2, gastroesophageal varices type 1+2; HE, hepatic encephalopathy; HRS, hepatorenal syndrome; HSC, hepatic stellate cells; HVPG, hepatic venous pressure gradient; ICU, intensive care unit; IGV1+2, isolated gastric varices type 1 +2; ISMN, isosorbide-5-mononitrate; LSM, liver stiffness measurements; MRI, magnetic resonance imaging; NASH, non-alcoholic steatohepatitis; NO, nitric oxide; NSBB, non-selective beta-blockers; OCA, obeticholic acid; PPG, portal pressure gradient; PTFE, polytetrafluoroethylene; RCT, randomized controlled trial; SBP, spontaneous bacterial peritonitis; SEC, sinusoidal endothelial cells; TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt; VEGF, vascular endothelial growth factor John Wiley & Sons A/S. Published by John Wiley & Sons Ltd wileyonlinelibrary.com/journal/liv Liver International 2017; 37(Suppl. 1):

2 BRUNNER et al. 105 Portal hypertension is defined as an increased portosystemic pressure gradient (difference between pressures in the portal vein and the inferior vena cava), which can be evaluated clinically by measuring the hepatic venous pressure gradient (HVPG) through hepatic vein catheterization. 1 This review will only focus on portal hypertension due to chronic liver disease (sinusoidal portal hypertension), which is the leading aetiology, followed by schistosomiasis (in developing countries), portal and splenic vein thrombosis, Budd- Chiari syndrome and other less frequent conditions due to presinusoidal or post- sinusoidal block. Portal hypertension is defined by a HVPG>5 mm Hg, but the risk of developing GEV and the clinical complications of decompensated chronic liver disease (e.g. ascites, variceal bleeding and overt HE) are only present when it reaches 10 mm Hg. 2 Thus, HVPG 10 mm Hg is called clinically significant portal hypertension (CSPH). At diagnosis, up to half of the patients with compensated cirrhosis have developed GEV. This is even more frequent in patients with severely impaired liver function (Child- Pugh class B/C). 3 GEVs develop with an annual incidence of 5%- 9% in patients without varices at diagnosis. 4,5 The rate of progression from small to large varices is similar. Prospective studies in the 1980s showed that the risk of first variceal bleed increases with impairment of liver function, size of varices and presence of red colour signs over the varices (red wales, red spots, diffuse redness) with an annual risk of approximately 12% (5% for small varices and 15% for large varices). 6,7 Bleeding from ruptured GEV is a major medical emergency, with a 6- week mortality of approximately 15% especially patients with poor liver function (Child- Pugh C). In many cases, death does not occur due to bleeding, but to infections, HRS and liver failure because of the bleeding episode. In the last three decades, improvement in evidence- based- guided treatment of portal hypertension and management of acute bleeding episodes has cut the mortality due to GEV bleeding in half. 8 Key points Treatment of portal hypertension must take into account the clinical stage of chronic advanced liver disease. Non-selective beta-blockers remain the cornerstone of the prevention of variceal bleeding, re-bleeding and other complications of portal hypertension, and they improve survival in patients with optimal hemodynamic response. Major advances include the use of carvedilol for primary prophylaxis of variceal bleeding and the use of statins combined with NSBB and EVL to reduce mortality in patients who have bled from variceal rupture. TIPS is now used early after a first episode of bleeding in high-risk patients, as a life-saving procedure in massive bleeding, and to prevent rebleeding in patients not responding to standard therapy (NSBB + EVL). increases if it is combined with other data suggesting portal hypertension, such as a reduced platelet count and increased spleen size in the so- called LSPS index. 11 The non- invasive diagnosis of CSPH in a patient without varices can also be made by detecting portal- systemic collaterals with imaging techniques (ultrasound, CT or MRI). The latest Baveno consensus conference recommends that patients with an LSM value 20 kpa and/or a decreased platelet count (<150 G/L) undergo endoscopic screening for the presence of GEV, while patients with both LSM<20 kpa and platelet count >150 G/L can safely skip endoscopy due to the low risk of having varices requiring treatment. 10 Based on the natural history of the disease, ACLD/cirrhosis can be classified into five stages according to the presence or absence of complications (Table 1). 12,13 2 STAGES OF CIRRHOSIS AND PORTAL HYPERTENSION: FROM FIBROSIS TO CLINICALLY SIGNIFICANT PORTAL HYPERTENSION In chronic liver disease, fibrosis progresses leading to cirrhosis and continues to worsen as long as the aetiologic factor is present. In daily practice, liver fibrosis is usually measured non- invasively by determining liver stiffness to assess the degree of fibrosis without a biopsy. 9 Since cirrhosis is an anatomical diagnosis requiring a liver biopsy, the term compensated advanced chronic liver disease (cacld) has been suggested rather than cirrhosis. 10 In asymptomatic compensated patients, values below 10 kpa on liver stiffness measurements (LSMs) by transient elastography (TE) exclude cacld, while values between 10 and 15 kpa suggest sacld but are not diagnostic, and correspond to a grey zone, and cacld is very likely in patients with values above 15 kpa. 10 Liver stiffness measurements have also been found to correlate with the presence of CSPH (values >13 suggest cirrhosis, and >20 are almost pathognomonic). The diagnostic accuracy of elastography 3 PATHOPHYSIOLOGY OF PORTAL HYPERTENSION AND ITS CHANGE WITH DISEASE PROGRESSION The pathophysiology of portal hypertension is essentially based on applying Ohm s law to hemodynamics: Pressure Gradient=Resistance Flow. Thus, portal hypertension may be due to increased resistance to portal blood flow, increased blood flow through the portal- collateral system or a combination of both (Figure 1). In ACLD, increased resistance to portal blood flow occurs not only because of the obvious architectural changes in the liver vasculature (fibrosis, nodules, angiogenesis and sinusoidal remodelling) but also due to dynamic changes in the sinusoids. Once they have been activated through inflammatory signalling or other stimuli, the adjacent hepatic stellate cells (HSCs), which reside in the space of Disse (virtual space between hepatocytes and sinusoidal endothelial cells [SECs]), begin to deposit extracellular matrix proteins and collagen. Microthrombi in small hepatic veins aggravate the structural component by causing hepatocyte drop- out and areas of parenchymal

3 106 BRUNNER et al. TABLE 1 Stages of advanced chronic liver disease Characteristics Stage 1a Stage 1b Stage 2 Stage 3 Stage 4 Stage 5 Compensated without varices Compensated without varices Compensated with varices Variceal bleeding without any other complication First non- bleeding decompensation (e.g. ascites, HE, jaundice) No CSPH CSPH CSPH CSPH CSPH CSPH Any second decompensating event 1-y mortality 1.5% 2% 10% 21% 87% 5- y- mortality Complications (annual incidence) 7% GEV 4% Ascites 6.6% Ascites 4% GEV bleeding 21% Progress to stage 4 10% Progress to stage 5 CSPH, clinically significant portal hypertension (HVPG>10 mm Hg); GEV, gastroesophageal varices; HE, hepatic encephalopathy. extinction. This structural component is thought to account for about 70% of the increased hepatic resistance to portal blood flow. The remaining 30% is a dynamic component including active contraction of activated HSC wrapped around sinusoids, myofibroblasts in the portal tracts, and vascular smooth muscle cells in the hepatic vasculature. In response to chronic liver damage, the SECs lose their fenestrae, which normally allow passive transport of macromolecules from the sinusoidal lumen to hepatocytes. A basement membrane develops along the sinusoidal surface of liver SEC, leading to capillarization of sinusoids that exhibit endothelial dysfunction. Endothelial dysfunction is characterized by impaired release of vasodilatory agents, mainly nitric oxide (NO) by the endothelial NO synthase (e- NOS). In a setting of increased vasoconstrictor drive due to increased endothelin production, activated renin- angiotensin and adrenergic systems and enhanced release of thromboxane A2, the lack of sufficient NO results in hepatic vasoconstriction further increasing hepatic resistance and worsening portal hypertension (Figure 1). 14 More advanced portal hypertension with the presence of portalsystemic collaterals (stage 2) is accompanied by splanchnic vasodilation, increased inflow of blood into the splanchnic organs draining into the portal venous system and increased portal- collateral blood flow. Vasodilation is mediated by increased release of vasodilators, including NO, carbon monoxide, endogenous cannabinoids and vasodilatory peptides of splanchnic origin such as glucagon. This is the opposite of the intrahepatic circulation (which exhibits vasoconstriction) and represents an adaptive homeostatic response to maintain portal perfusion of the liver, which is reduced by the development of prehepatic and intra- hepatic portal- systemic shunts. However, the increased portalcollateral blood flow further worsens portal hypertension, accelerating the development of collaterals causing further splanchnic vasodilation, creating a vicious cycle. Severe splanchnic vasodilation may result in peripheral resistance and hypotension and effective hypovolaemia, causing activation of endogenous vasoactive systems, which trigger plasma volume expansion (Figure 1). This expanded plasma volume and the additional blood volume returning from the portal- systemic collaterals to the right atrium promotes increased cardiac output and a full- blown hyperkinetic syndrome. In stages 3 and 4, vasodilation is so intense that clinical sodium retention is triggered and located in the peritoneal cavity in the form of ascites (Figure 1). Collateral formation is not only caused by increased portal pressure, but requires active angiogenesis, driven by vascular endothelial growth factor (VEGF). VEGF not only activates among others the enos signalling pathway, but also promotes the formation of portosystemic collaterals and GEV. Physiologically, portosystemic collaterals are shunts between the portal and the systemic circulation that contribute to the hyperkinetic systemic circulation and hepatic encephalopathy as well as impaired metabolism of drugs and toxins. 4 Current treatments for portal hypertension (Table 2) 4.1 Non- selective beta- blockers (NSBBs) remain the cornerstone of prevention of bleeding Traditional NSBB have been used for more than 30 years Standard NSBBs (propranolol, nadolol and timolol) decrease portal pressure by reducing portal- collateral blood flow through reduction of the cardiac index (via beta1- receptor blockade) and splanchnic vasoconstriction (via beta2- adrenoceptor blockade). 5,15 Therefore, hyperkinetic circulation is necessary for them to act. For more than 30 years, NSBBs have been shown to effectively prevent a first GEV bleed and recurrence of GEV bleeding, as well as to lower bleedingassociated mortality. 16,17 Moreover, NSBBs increase intestinal transit time, reduce bacterial translocation and lower the risk of spontaneous bacterial peritonitis. 18 To effectively prevent variceal bleeding, NSBB should reduce the HVPG to 12 mm Hg or below (optimal response) or at least by 20% of its baseline value (good hemodynamic response). However, a long- term satisfactory hemodynamic response is only obtained in 33%- 50% of patients with NSBB. In non- responders, addition of low doses of an NO- donor such as isosorbide- 5- mononitrate (ISMN) causes an additional decrease in portal pressure, while increasing side effects. 19,20 However, the fixed combination of NSBB and ISMN is not clearly better than NSBB alone in preventing a first episode of GEV bleeding, but in an à la carte HVPG- guided approach, the addition of ISMN has been shown to rescue about one third of non- responders to NSBB. 20,21 The recommended dosages of NSBB and most frequent side effects are listed in Table 2.

4 BRUNNER et al. 107 is sustained for several hours. 25 Due to its long biological activity, terlipressin can be administered every 4 hours as repeat intravenous injections, although if it is given as a continuous infusion the total dose may be decrease. Due to the intravenous administration of this agent, it is only used for short periods, which in practice is limited to the treatment of acute variceal bleeding (2-5 days) or type- I hepatorenal syndrome (1-2 weeks). Because of the potential ischaemic and arrhythmic complications, terlipressin should not be used in patients with a history of coronary, cerebrovascular, peripheral or visceral arterial diseases. Also, it should be used with caution in elderly and/or hypertensive patients. 4.3 Somatostatin and long- acting somatostatin analogues are also potent splanchnic vasoconstrictors FIGURE 1 Pathophysiology of portal hypertension and potential targets for drug therapy Carvedilol is more effective than propranolol/nadolol In addition to its capacity to block beta1- and beta2- receptors, the NSBB carvedilol has an intrinsic anti- α- adrenergic activity and the potential to release NO. This is why it is more effective in lowering portal hypertension than propranolol/nadolol after acute or chronic administration (in a face- to face randomized comparison, the mean HVPG decrease was 22.2% vs 15.6% respectively). 22 Moreover, more than half (56%) of non- responders to standard NSBB therapy achieve a good hemodynamic response with carvedilol. In the same study, the use of propranolol as a first- line primary prevention followed by carvedilol in those who did not hemodynamically respond to propranolol resulted in a good hemodynamic response in 72%. 23 Low doses of carvedilol (<25 mg/day) are as effective as relatively high doses (25-50 mg/day) in decreasing HVPG. Low doses (12.5 mg/day) of carvedilol are, therefore, recommended, as high doses can cause arterial hypotension, which may enhance sodium retention and worsen ascites. In a primary prophylaxis randomized controlled trial, carvedilol prevented a first GEV bleeding episode more effectively than repeat EVL, although this requires confirmation in further studies Terlipressin is used for acute bleeding Terlipressin a long- acting synthetic vasopressin analogue is a potent splanchnic vasoconstrictor that also has systemic circulatory effects, increasing arterial pressure and systemic vascular resistance, and decreasing cardiac output. A single intravenous administration leads to a marked decrease in the HVPG of more than 25%, which Somatostatin is also an effective splanchnic vasoconstrictor that effectively decreases portal pressure through the inhibition of glucagon and other vasoactive peptides and the facilitation of adrenergic vasoconstriction. 25,26 Because of its very short half- life (1-3 minutes), it should be administered in a continuous intravenous infusion. Dose- response studies have shown that to significantly decrease both HVPG and portal- collateral (azygos) blood flow, a dose of 500 μg/hour is required. 27 Long- acting analogues (octreotide, vapreotide, and lanreotide) have been developed to overcome the short half- life of somatostatin. After a bolus of octreotide the, HVPG markedly decreases in a manner similar to somatostatin (around 50%), but this effect is short and decreases with repeated administration. The decrease in the HVPG is not maintained by a continuous intravenous infusion, but limits the postprandial increase in portal pressure in patients with portal hypertension. However, this only partially explains why octreotide successfully controls GEV bleeding New drugs Statins may improve survival Statins improve endothelial dysfunction in many vascular diseases due to its beneficial pleiotropic circulatory effects. Most effects are due to enhanced expression of the KLF- 2 transcription factor and reported genes (enos, thrombomodulin and angiopoietin). In experimental cirrhosis, statins (simvastatin and atorvastatin) decrease hepatic vascular resistance, improve endothelial dysfunction and decrease fibrosis. In patients with cirrhosis, statins moderately lower HVPG (even in patients being treated by NSBB) and improve quantitative liver function tests but do not influence the systemic circulation. 29 In a recent RCT in patients who survived an episode of variceal bleeding adding simvastatin to the standard of care (NSBB and EVL) did not improve the prevention of variceal rebleeding, but improved survival, mainly by reducing the number of deaths due to bleeding and infections. 30 Large epidemiological surveys have shown that the progression of liver disease is reduced and mortality decreased in patients with cald receiving statins. 31

5 108 BRUNNER et al. TABLE 2 Drugs for the treatment of portal hypertension Propranolol Nadolol ISMN Carvedilol Terlipressin Somatostatin Octreotide Simvastatin Beta- 1 and beta- 2 adrenergic receptor antagonist (NSBB) Beta- 1 and beta- 2 adrenergic receptor antagonist (NSBB) No donor Beta- 1 and beta- 2 adrenergic receptor antagonist (NSBB) with intrinsic anti- α1 activity Long- acting vasopressin analogue Splanchnic vasoconstriction, increase in systemic vascular resistance Peptide hormone, inhibits glucagon and facilitates adrenergic vasoconstriction Long- acting SMT analogue Improves endothelial dysfunction and reduces intra- hepatic vascular resistance Route Oral Oral Oral Oral Intravenous Intravenous Intravenous Oral Dosage Start with mg twice daily Increase the dose every 2-3 d up to the maximal tolerated dose Systolic blood pressure should remain 100 mm Hg and HR 50 bpm Start with 20 mg daily Increase the dose every 2-3 d up to the maximal tolerated dose Systolic blood pressure should remain 100 mm Hg and HR 50 bpm Start with 10 mg daily at night Increase the dose after 2-3 d up to 20 mg twice a day Start with mg twice daily Increase the dose every 2-3 d up to 12.5 mg/d Systolic blood pressure should remain 100 mm Hg and heart rate 50 bpm 2 mg injection every 4 h for h, then 1 mg/4 h for up to 5 d Bolus 250 μg followed by continuous i.v. infusion μg/h for up to 5 d Bolus 50 μg i.v., followed by continuous i.v. infusion 50 μg/h for up to 5 d 20 mg once a day. After 2 wk, increase to 40 mg/d if CPK and ALT do not increase over twice the baseline values Max dose 320 mg/d 160 mg/d 40 mg/d 25 mg/d 8 mg/d for h 4 mg/d thereafter 500 μg/h 50 μg/h 40 mg/d Side effects Bradycardia, orthostatic hypotension, Bronchospasm, erectile dysfunction Bradycardia, orthostatic hypotension, bronchospasm, erectile dysfunction Headache, orthostatic hypotension Arterial hypotension, Sodium retention, ascites Abdominal pain, arterial hypertension; less than 3% ischaemia (peripheral, intestinal or myocardial) Hyperglycaemia, vomiting Hyperglycaemia, vomiting Elevated aminotransferases (not more frequent than in the general population) Up to 3% rhabdomyolysis in advanced cirrhosis (bilirubin >5 mg)

6 BRUNNER et al Renin- angiotensin- aldosterone inhibitors: more studies needed Cyanoacrylate injection Although NSBB and ACE inhibitors and angiotensin receptor blockers lower the HVPG at a nearly similar rate and appear to be safe in patients with good liver function (Child- Pugh A), 32 the role of these agents in preventing GEV bleeding and the safety profile in decompensated ACLD require further studies. EVL Aetiologic treatments reduce portal pressure with time Studies in several liver diseases (hepatitis B, hemochromatosis, hepatitis C, alcoholic liver disease) have shown that successful specific treatment of liver disease can markedly reduce portal pressure. The time necessary for this beneficial effect varies and is probably longer in clinically decompensated patients. This is highly relevant since the introduction of direct acting antivirals for hepatitis C virus infection, which is one of the main causes of cirrhosis worldwide. It is still uncertain whether the risk of portal hypertension- related complications will completely disappear, when this will occur and how it can be non- invasively detected, but these elements are being evaluated in large prospective studies. Cyanoacrylate injection GOV 1 GOV 2 Cyanoacrylate injection Antifibrotic drugs are promising Obeticholic acid (OCA) is a Farnesoid X receptor agonist, a nuclear receptor in the liver and intestine that suppresses bile acid synthesis and increases the transport of bile acids from hepatocytes into the canaliculi. OCA significantly improves liver biochemistry in patients with primary biliary cholangitis who do not respond to treatment with ursodeoxycholic acid. OCA also improves the histological features of patients with non- alcoholic steatohepatitis (NASH). Further trials in the field of primary biliary cholangitis, NASH, primary sclerosing cholangitis and biliary atresia are ongoing. 33 Simtuzumab, a monoclonal antibody directed against lysyl oxidaselike 2 (LOXL2) enzyme, was developed to target changes in fibrosis. In a mouse model, simtuzumab reduced bridging fibrosis, total collagen expression and improved survival. In a recent open- label safety trial, 6 months of treatment with this agent was well tolerated in patients with hepatitis C and/or HIV and advanced fibrosis, but did not affect liver histology. 34 A large RCT in patients with NASH- related cirrhosis examining the long- term effects of simtuzumab on liver histology and HVPG is in progress. Emricasan, an anti- apoptotic agent with anti- inflammatory and antifibrotic properties, has been shown to decrease portal pressure in a recent pilot study in patients with cirrhosis 35 as well as in experimental models. 4.5 Endoscopic therapy: band ligation for oesophageal varices and obliteration for gastric varices Endoscopic variceal band ligation (EVL) is the endoscopic treatment of choice for oesophageal varices (EV) because it is more effective and safer than endoscopic injection sclerotherapy (EIS). 36 Once IGV 1 IGV 2 FIGURE 2 Gastroesophageal and isolated gastric varices: classification according to Sarin 55 and choice of endoscopic treatment [Colour figure can be viewed at wileyonlinelibrary.com] EVL is begun for acute bleeding or scheduled primary/secondary prophylaxis, it should be repeated every 2-4 weeks until complete eradication of the varices is obtained. The term eradication is not literally the absence of varices, but defines varices that are absent or small ( remnants ) and cannot or need not be further ligated. This definition, therefore, involves a subjective component. After eradication, endoscopic screening at 1, 6, 12 months, and every 12 months thereafter is recommended to detect recurrent high- risk varices Endoscopic therapy for gastric varices Isolated gastric varices (IGV1 and 2) and type 2 gastroesophageal varices (GOV2), which reach the stomach from the oesophagus on the side of the greater curvature (Figure 2), should be treated by endoscopic variceal obliteration with intravariceal injection of a tissue adhesive (e.g. n- butyl- 2- cyanoacrylat). This has been shown to be more effective than band ligation in acute bleeding from gastric varices. A second glue injection into IGV 2-4 weeks later can be considered to further reduce the risk of re- bleeding. Although gastroesophageal varices type 1 (GOV1), which extend into the stomach on the side of the lesser curvature, are usually treated with EVL, centres in Asia support using variceal obliteration with glue injection (Figure 2). 10 Thrombin has been used instead of glue. 37

7 110 BRUNNER et al. 4.6 Interventional radiology treatments: intrahepatic shunts and retrograde obliteration of varices Transjugular intrahepatic portosystemic shunt (TIPS) is a minimally invasive fluoroscopic- guided procedure that creates a shunt between a hepatic vein and the intrahepatic portal vein sustained by a metal stent. TIPS is a portosystemic shunt that is large enough to effectively decrease portal pressure and small enough not to cause liver failure and hepatic encephalopathy. Ideally, it should maintain a portal pressure gradient (PPG, the difference between portal and inferior vena cava pressure) between 10 and 12 mm Hg. This requires progressive dilatation of the stent with balloon angioplasty catheters (usually up to 8-10 mm in diameter) while measuring the PPG. The use of stents covered with polytetrafluoroethylene (PTFE) is recommended to prevent occlusion of the shunt and maintain rates of primary unassisted patency similar to those of surgical shunts. 38 TIPS has almost completely replaced surgical shunts because of the reduced surgical morbidity and mortality and similar efficacy. The main indications for TIPS are the treatment of acute variceal bleeding (as preventive therapy in high- risk patients or as rescue therapy after failure of medical plus endoscopic treatment) and refractory ascites. TIPS is more effective than alternative therapy in both these indications and may decrease mortality. Evaluation of TIPS candidates should include a detailed history of previous episodes of HE, assessment of portal vein patency and anatomy on imaging, absence of biliary dilatation or tumours in the intrahepatic tract, and a transthoracic echocardiography. Because of the risk of cardiac decompensation, TIPS is contraindicated in patients with congestive heart failure, severe pulmonary hypertension and tricuspid regurgitation. Recurrent episodes of HE, portal vein thrombosis and hepatocellular carcinoma are relative contraindications. HE is more frequent in patients over 70 or with large bore shunts (12 mm or more in diameter). 38. HE occurs in about one third of the cases. Although in most cases it can be managed medically, in about 6%- 10% of patients HE is severe and may require closure or reduction of TIPS. 39 Balloon- occluded retrograde transvenous obliteration (BRTO) is another minimally invasive procedure in which gastric or mesenteric varices are retrogradely accessed from the femoral vein via a spontaneous splenorenal shunt and occluded with tissue adhesives or thrombogenic intravascular coils. This method has been found to be very efficient in controlling acute bleeding from gastric varices, but no randomized controlled trials are available. It should be considered when endoscopic and medical therapies fail and the patient is not a good candidate for TIPS CLINICAL SCENARIOS FOR THERAPY The treatment of varices and variceal haemorrhage vary based on the clinical scenario and the previously described stages of ACLD. An overview of the different treatment strategies is provided in Table Compensated patients without gastroesophageal varices: prefer aetiologic treatments In early stages, the goal of treatment is to avoid the progression of cirrhosis to hepatic decompensation by preventing a further increase in portal hypertension. In this early stage, the aetiologic factors can be targeted (e.g. antiviral treatment, alcohol withdrawal, weight loss, phlebotomies and chelator therapy). Successful antiviral treatment may lead to improvement of fibrosis, thus improving portal hypertension, although little is still known about how long this can take, if there are no- return points, and how this resolution can be assessed noninvasively. Exercise and weight loss have been reported to decrease HVPG in obese patients independently of the underlying cause. 41 Also, patients with ACLD should abstain from alcohol. 10 The results of a large study in cacld on the so- called preprimary prophylaxis of the development of GEV by long- term administration of timolol (a NSBB) were negative. 5,15 However, this study importantly showed that risk of developing varices, and especially ascites, bleeding or hepatic encephalopathy, is more frequent in compensated patients with CSPH (HVPG of at least 10 mm Hg). Accordingly, the recommendations from the most recent Baveno conference state that the goal of therapy in these patients should be the prevention of decompensation. The preliminary results of a multicentre randomized controlled trial (ClinicalTrials number: NCT ) designed for this purpose suggest that the long- term administration of propranolol (or carvedilol in patients whose HVPG does not decrease by at least 10% from baseline after intravenous propranolol) may prevent decompensation- free survival and almost halve the incidence of ascites. 5.2 Compensated Patients with Varices Patients with small varices and no other risk factors for bleeding: beta- blockers The use of NSBB could be beneficial in patients with small (<5 mm) EV without red colour signs and good/moderate liver function (Child- Pugh A/B), but this must be confirmed in further trials Patients with high- risk varices (primary prophylaxis of variceal bleeding): betablockers or ligation These include patients with small EV, but with red colour signs and/or Child- Pugh C, and patients with medium or large (>5 mm) EV. The goal of therapy is to prevent first variceal bleeding and other complications from portal hypertension thus improving survival. In patients with high risk but small varices, primary prophylactic treatment with carvedilol or a standard NSBB can be initiated. In patients with medium or large varices (>5 mm), primary prophylaxis can be provided using either standard NSBB or carvedilol or EVL. EVL is as effective and can be used as an alternative to NSBB based on local resources and patient preferences. In general, EVL is the preferred option in patients with contraindications or intolerance

8 BRUNNER et al. 111 TABLE 3 Overview of treatment goals and strategies for portal hypertension according to the clinical scenario Clinical scenario Goal of treatment Baveno recommendations regarding screening and surveillance endoscopy Accepted pharmacological therapies and general measures Compensated patients in whom CSPH has been excluded by HVPG measurement Prevent Progression to CSPH No need for screening of varices (no CSPH). Aetiologic therapy (e.g. alcohol withdrawal, antiviral therapy, weight reduction if overweight/obese) Compensated patients with likely or confirmed CSPH (LSM>20 kpa and/or platelet count<150 G/L, or with measured HVPG 10 mm Hg) Prevent development of varices Prevent decompensation Screen for varices If no varices are seen: repeat endoscopy after 2 or 3 y, depending on presence or absence of ongoing liver damage if varices are present: see below Aetiologic therapy (e.g. alcohol withdrawal, antiviral therapy, weight reduction if overweight/obese) Compensated patients with small varices without RCS in Child- Pugh A/B Prevent decompensation Stabilize/lower portal pressure in order to reduce the risk of variceal progression Repeat endoscopy after 1 or 2 y, depending on the presence or absence of ongoing liver damage Aetiologic therapy (e.g. alcohol withdrawal, antiviral therapy, weight reduction if overweight/obese) NSBB can be considered a Compensated patients with small varices with RCS AND decompensated patients Child C with small varices Prevent the first variceal bleeding episode Prevent decompensation if compensated Prevent further decompensation if decompensated Begin NSBB or carvedilol No further endoscopies needed Aetiologic therapy (e.g. alcohol withdrawal, antiviral therapy, weight reduction if overweight/obese) NSBB/carvedilol Any patient with EV at least medium/large in size or with gastric varices Prevent the first variceal bleeding episode Prevent decompensation if compensated Prevent further decompensation if decompensated Begin NSBB or carvedilol EVL if intolerant or contraindications to NSBB No further diagnostic endoscopies needed For patients on EVL: repeat ligation every 2-4 wk until complete eradication of EV, afterwards 1, 6, 12 mo and every year Aetiologic therapy (e.g. alcohol withdrawal, antiviral therapy, weight reduction if overweight/obese) NSBB/carvedilol Acute variceal bleeding Achieve haemostasis Prevent rebleeding within 5 d Minimize 6- wk mortality N/A Vasoactive drugs and prophylactic antibiotics Restrictive transfusion policy Perform endoscopy within 12 h (achieve stabilization first) EVL for EV and cyanoacrylate injection for GOV2/IGV Consider SEMS for refractory/massive bleeding Consider early TIPS in high- risk patients (Child- Pugh C<13 points or Child B with active haemorrhage) and in patients with early rebleeding within 5 d Prevention of recurrent bleeding after first haemorrhage Prevent recurrent bleeding Prevent other decompensation Improve survival Repeated EVL every 2-4 wk until complete eradication, afterwards 1, 6, 12 mo and every year First option (standard): NSBB b +/ ISMN plus EVL If repeated EVL not possible: NSBB+/ ISMN if NSBB not tolerated: consider TIPS Consider adding simvastatin After bleeding from gastric varices: consider TIPS CSPH, clinical significant portal hypertension; EV, oesophageal varices; EVL, endoscopic variceal band ligation; GOV, gastroesophageal varices; HVPG, hepato- venous pressure gradient; IGV, isolated gastric varices; ISMN, isosorbide- 5- mononitrate; NSBB, non- selective beta- blockers; RCS, red colour signs; SEMS, self- expandable metal stent. a Insufficiently explored. b Role of carvedilol not yet defined.

9 112 BRUNNER et al. to NSBB (after trying to switch to carvedilol, which is usually better tolerated). However, contrary to NSBB, EVL does not prevent other complications of portal hypertension, such as bleeding from portal hypertensive gastropathy or colopathy, ascites and SBP. 10,41,42 Gastric varices without previous bleeding can also be treated with NSBB Treatment of acute bleeding Acute variceal haemorrhage is a medical emergency that requires prompt and intensive medical care, ideally in an ICU. Initial management should target control of the haemorrhage, prevent early (within 5 days) re- bleeding, deterioration of liver function and other bleedingrelated complications, mainly infections, acute kidney injury and HE GENERAL MANAGEMENT: RESUSCITATION, ANTIBIOTICS AND PREVENTION OF ENCEPHALOPATHY Resuscitation measures should follow the classical ABC (Airway, Breathing, Circulation) principle to restore hemodynamic stability and to maintain appropriate delivery of oxygen to the tissues. Airway protection with orotracheal intubation is mandatory in unconscious patients or those with severe haemorrhage (hematemesis) before endoscopy to prevent airway aspiration. Plasma volume expansion is primarily infused for volume replacement. Packed red blood cells should be transfused restrictively (target haemoglobin level 7 g/dl), because a less restrictive policy (target haemoglobin 9 g/dl) can increase mortality. 43 This restriction does not apply to Child C patients, in cases of rapid ongoing bleeding or patients with a history of ischaemic cardiovascular disease. Early prophylactic antibiotics, to prevent the occurrence of infections after a bleeding episode and improve survival should be also started on admission. 44 The Baveno consensus conference recommends the use of intravenous ceftriaxone 1 g/24 hours in patients with advanced cirrhosis, in areas with high prevalence of quinoloneresistant bacterial infections and in patients on previous quinolone prophylaxis. The choice of the ideal antimicrobial prophylaxis must be made in each centre depending on local antibiotic resistances. Also, the patient s individual risk factors (e.g. advanced cirrhosis and previous infections) must be taken into account. 10 Furthermore, patients with signs of infection on admission should be extensively evaluated and treated. Prevention of HE: Lactulose per os, via a nasogastric tube or rectally, is recommended to prevent HE. Rifaximin may also be effective, but has not been specifically investigated yet in these cases SPECIFIC THERAPY: FROM VASOACTIVE DRUGS TO TIPS Vasoactive drugs When variceal haemorrhage is suspected, intravenous vasoactive therapy (terlipressin, somatostatin or octreotide) should be begun. This is usually started on arrival in the emergency room, before endoscopy. All drugs are thought to be equally effective in controlling bleeding and preventing re- bleeding within 5 days, but the quality of the evidence varies, because terlipressin is the only drug that has been shown to be effective to control bleeding, decrease transfusion requirements and reduce the 6- week mortality in placebo- controlled clinical trials. 45 A recent large face- to- face study that showed equal efficacy should be considered with caution because subtherapeutic doses of terlipressin and suboptimal doses of somatostatin were used. 46 Recommended doses are given in Table 2. Vasoactive drug infusion is maintained for 2-5 days Endoscopic therapy Emergency endoscopy should be scheduled as soon as possible, at the latest 12 hours after admission; 250 mg erythromycin intravenously prior to endoscopy accelerates the gastric emptying of clots and improves visibility during the endoscopy. 10 A positive diagnosis of variceal bleeding requires endoscopic confirmation of active bleeding from varices, the presence of a fibrin clot ( white nipple sign) signalling the point of variceal rupture, or blood in the stomach with varices as the only potential source of the bleeding. EVL is indicated in endoscopically demonstrated variceal bleeding and should be performed immediately (at the diagnostic endoscopy) by an experienced endoscopist. If the bleeding originates from GOV2 or IGV variceal obliteration is preferred with injection of tissue adhesives. Recommended treatment with combined vasoactive drugs and endoscopic therapy (plus prophylactic antibiotics) results in successful 5- day control of bleeding in 85%- 90% of cases. After this period, NSBB treatment can be begun as secondary prophylaxis (see section 5.4) Preemptive TIPS The above treatment strategy does not stratify therapy for the known risk factors. These are the presence of advanced liver failure (Child- Pugh C), active bleeding at endoscopy despite vasoactive drug infusion and very high portal pressure (HVPG 20 mm Hg). A multicentre RCT recently has shown that making an early decision to perform a PTFE- covered TIPS (during the first hours of admission), before declaring treatment failure, resulted in decreased failure to control bleeding, rebleeding and mortality in high- risk patients. 47 Patients were either Child- Pugh class C (<14 points) or Child- Pugh class B and with active bleeding on endoscopy, with no contraindications to TIPS. Further studies have confirmed the findings of this important report, but showed that survival is especially improved in class C patients. 48 This approach is now recommended for approximately 20% of patients who fulfil these criteria and are treated in centres with enough experience with these procedures Treatment of patients that fail standard therapy ( Rescue Therapy ) The most demanding situation is the treatment of patients in whom standard therapy with vasoactive drugs and endoscopic treatment

10 BRUNNER et al. 113 fails to control bleeding or the bleeding begins again within 5 days. The recommended therapy in these cases is to perform an emergency TIPS, if there is no contraindication. In case of non- severe rebleeding within 5 days, treatment with vasoactive drugs is continued and a second attempt with endoscopic therapy can be made before a rescue TIPS is considered. Rescue TIPS is very effective in controlling bleeding, but it is still associated with a high mortality of about 40%, probably because liver function markedly deteriorates during uncontrolled bleeding until the TIPS is finally performed. BRTO may be considered in patients with refractory bleeding from gastric varices and a contraindication to TIPS Oesophageal Tamponade Balloon tamponade with a Sengstaken- Blakemore or a Linton- Nachlas tube may still be used in the very rare case of massive exsanguinating bleeding or recurrent bleeding as a bridge to TIPS or another definitive treatment. However, oesophageal self- expandable metallic stents have been shown to be very effective 49 and a recent RCT showed that oesophageal stents are as effective but safer than balloon tamponade. 50 This is part of current recommendations PATIENTS WHO SURVIVE AN EPISODE OF VARICEAL BLEEDING: BETA- BLOCKERS, LIGATION AND TIPS This clinical setting includes the so- called secondary prophylaxis of variceal haemorrhage, but as mentioned in the paragraph on primary prophylaxis, the concept of improving outcomes in variceal bleeding is evolving since the goal of therapy in these cases is to reduce the risk of death, and thus prevent the onset of complications of cirrhosis that can lead to death. They include re- bleeding, but should not be limited to this, and all of them should be taken into account as endpoints in future RCTs in this setting. The goal of secondary prophylaxis of variceal bleeding is to prevent recurrent variceal haemorrhage once the first episode of bleeding has been under control for at least 5 days, since the risk of rebleeding is high (60% within first year) and associated with high mortality (up to 33%). 41 The first- line treatment includes standard NSBB lifelong plus EVL until complete eradication of varices. As shown in a recent meta- analysis, this combination is better than EVL alone to prevent bleeding, but only slightly better than pharmacological therapy alone and has no effect on survival. 51 Thus, NSBBs (combined with nitrates if tolerated) are the cornerstone of treatment. The most favourable outcome is observed in patients with a good hemodynamic response to NSBB, namely those in whom the HVPG is decreased by at least 20% or below 12 mm Hg on treatment. 52 The HVPG response should be measured regularly for better risk stratification and to guide therapy in experienced centres. Because EVL alone does not seem to provide sufficient protection from bleeding, TIPS should be considered in patients who do not tolerate NSBB rather than EVL alone, in particular if other complications such as ascites or portal vein thrombosis have already occurred. In secondary prophylaxis, the use of carvedilol is not recommended, because data from RCT comparing carvedilol with NSBB in combination with EVL are lacking. Statins provided additional survival benefit in patients who survived an episode of variceal bleeding included in a recent multicentre RCT, and should be considered in patients without severe liver failure (benefit in Child C patients is unclear). 30 PTFE- covered TIPS is better than standard secondary prophylaxis (NSBB + EVL) in reducing the risk of rebleeding and is indicated in patients with recurrent bleeding on standard medical and endoscopic therapy. However, TIPS does not improve survival and is associated with the development of HE in one third of patients. 53, Secondary prophylaxis in special situations Fundal and ectopic varices Transjugular intrahepatic portosystemic shunt is indicated for the prevention of rebleeding from fundal varices (GOV2 and IGV1). In expert centres, cyanoacrylate glue injection can be used as an alternative. In very selected cases (large gastro- or splenorenal collaterals), BRTO could be an option. Ectopic varices (IGV2), which are more frequent in non- cirrhotic portal hypertension, require a case- by- case assessment preceded by cross- sectional imaging to map collateral vessels Patients with complicated ascites Recent data have warned against the use of NSBB in decompensated patients with refractory ascites, HRS and/or SBP. Although data are not conclusive, these studies do not support the decision to stop NSBB in all patients with complicated ascites. Nevertheless, the recommendations of the Baveno VI consensus conference suggest that blood pressure, sodium levels and kidney function should be carefully monitored and NSBB should be temporarily discontinued or reduced in case of severe arterial hypotension, hyponatremia or acute kidney injury PERSONAL CONCLUSION The treatment of portal hypertension has markedly improved in the past years, and we now have successful therapies that have increased patient survival in each clinical scenario. This has been possible mainly by following a pathophysiological approach aimed at correcting the basic disturbance, the increased portal pressure, by improving the abnormalities causing it. There has been a continued systematic effort in converting each advance in knowledge into a new therapeutic target, in what should be considered an example of highly successful translational research. This has been done in parallel with careful clinical observations and cooperative efforts that have allowed better risk stratification and the definition and standardization of treatment endpoints, exemplified by the Baveno Consensus Conferences. We hope that merging translational and clinical research efforts in the recently

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