Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)

The Billroth III guidelines were developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (OGGH) and the Austrian Society of Interventional Radiology (OGIR) held on 18 February 2017 in Vienna. Based on international guidelines and considering recent landmark studies, the Billroth III recommendations aim to help physicians in guiding diagnostic and therapeutic strategies in patients with portal hypertension.

## I.
Definitions of portal hypertension II. Diagnosis and screening of portal hypertension III. Preprimary prophylaxis and prevention of decompensation IV. Primary prophylaxis of variceal bleeding V.
Acute variceal bleeding VI. Secondary prophylaxis of variceal bleeding VII. Measurement of the hepatic venous pressure gradient (HVPG) VIII. Portal hypertensive gastropathy IX. Gastric varices X.
Management of ascites XI. Spontaneous bacterial peritonitis (SBP)
The strength of the underlying evidence and the recommendations were based on a modified version of the GRADE system I. Definitions of portal hypertension [bib_ref] for the GRADE Working Group. GRADE: an emerging consensus on rating quality..., Guyatt [/bib_ref]. The term compensated advanced chronic liver disease (cACLD) may be used similar to cirrhosis and is defined as confirmed liver stiffness >15 kPa on transient elastography [bib_ref] Non invasive evaluation of portal hypertension using transient elastography, Castera [/bib_ref]. Diagnosis of cACLD should trigger screening for clinically significant portal hypertension (CSPH) [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 2. CSPH is defined as an increase of the hepatovenous pressure gradient (HVPG) to values of 10 mm Hg. (A1) [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] 3. Normal portal pressure is defined as HVPG of 5 mm Hg, while subclinical portal hypertension is defined as HVPG 6-9 mm Hg. (A1) 4. CSPH might already be present in compensated patients (without ascites, without varices). (A1) 5. The presence of gastroesophageal varices (GOVs), variceal hemorrhage, ascites (in the absence of significant cardiac, malignant, peritoneal or renal comorbidities) and/or the presence of large portosystemic collaterals on imaging studies are indicative of the presence of CSPH [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 6. Assessing the four Baveno stages of portal hypertension is clinically useful to quickly assess the prognosis of patients with liver cirrhosis: Baveno-I compensated, no varices, Baveno-II compensated, presence of GOVs, Baveno-III decompensated with ascites and Baveno-IV decompensated, history of variceal bleeding [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D&apos;amico [/bib_ref]. (B1) 1. Patients with cirrhosis (or cACLD) should be screened for CSPH [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] (see Billroth-III screening algorithm in [fig_ref] Figure 1: Flow chart for screening of varices in cirrhotic patients [/fig_ref]. (A2) 2. After the initial diagnosis of cirrhosis (or cACLD) screening endoscopy may be performed at least once if the patient never had an upper GI endoscopy before. (C1) 3. In cirrhotic patients with a platelet count >150 G/L and liver stiffness <15 kPa on transient elastography screening endoscopy can be safely deferred [bib_ref] Noninvasive tools and risk of clinically significant portal hypertension and varices in..., Abraldes [/bib_ref] [bib_ref] Liver stiffness plus platelet count can be used to exclude high-risk oesophageal..., Ding [/bib_ref] [bib_ref] Elastography, spleen size, and platelet count identify portal hypertension in patients with..., Berzigotti [/bib_ref]. (B1) 4. Esophageal varices (EV) should be graded as absent, small (<5 mm of diameter), or large (5 mm).
The presence of red spots should be indicated for risk stratification. (A2) 5. Gastric varices should be described as GOV-1 (continued varices on minor curvature), GOV-2 (continued varices on larger curvature extending to the fundus) or isolated gastric varices (IGV-1) isolated fundal varices or IGV-2 ectopic varices in the stomach. The presence of red spots should be indicated for risk stratification [bib_ref] Prevalence, classification and natural history of gastric varices: A long-term follow-up study..., Sarin [/bib_ref]. (B2) 6. In patients without varices, endoscopy should be repeated every 2 years in the case of compensated cirrhosis and every year in the case of decompensated cirrhosis [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (C1) 7. Patients with low-risk varices should receive nonselective beta blockers (NSBBs). (C1) 8. In compensated patients with varices (EV or receiving NSBBs there is no indication for endoscopic monitoring of the varices [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (C1) 9. If HVPG is measured as 10 mm Hg, endoscopy should be repeated every year in order to screen for the presence of varices, since CSPH is predictive of the formation of esophagogastric varices [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (A1) 10. There is no indication for subsequent endoscopic surveillance once large EVs or gastric varices (5 mm) are detected, unless endoscopic treatment is performed for primary or secondary prophylaxis of variceal bleeding [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref]. (B1)

## Iii. preprimary prophylaxis and prevention of decompensation
The effectiveness of NSBBs in the setting of preprimary prophylaxis (prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis; cACLD) has been addressed in a landmark study which randomly assigned patients with cirrhosis and portal hypertension (defined by HVPG 6 mm Hg; 63% had CSPH) to timolol or placebo [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref]. After a median follow-up of nearly 5 years, approximately 40% of patients in both groups met the composite primary endpoint of development of varices or variceal bleeding. Thus, in general, there is no indication for NSBBs treatment in patients who have not developed varices; however, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). In the aforementioned study, patients who had a relative HVPG decrease of >10% after 1 year showed a lower incidence of the primary endpoint [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref] ; however, relevant HVPG decreases during NSBBs treatment are only observed in patients with CSPH [bib_ref] Development of hyperdynamic circulation and response to beta-blockers in compensated cirrhosis with..., Villanueva [/bib_ref]. In a recent randomized controlled trial (RCT) restricted to patients with CSPH, preprimary prophylaxis (44%) or small varices without red spot signs (56%), propranolol/carvedilol decreased the risk of S136 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article hepatic decompensation, mostly by decreasing the incidence of ascites [bib_ref] A Randomized trial to assess whether portal pressure guided therapy to prevent..., Villanueva [/bib_ref]. Thus, future studies should address the potential benefits of early initiation of NSBBs (especially carvedilol) treatment in the subgroup of patients with CSPH.
1. Preprimary prophylaxis defines the prevention of the development of varices and variceal bleeding in patients with compensated cirrhosis (cACLD) who do not have varices. (A1) 2. In general, there is no indication for NSBBs treatment in patients with cACLD who have not yet developed varices. Nevertheless, NSBBs might be indicated for extrahepatic comorbidities (e. g. arterial hypertension, coronary heart disease, and heart failure). (A1) 3. Preprimary prophylaxis with NSBBs can be considered in patients with CSPH since it may reduce the risk of developing ascites. (B2)

## Iv. primary prophylaxis of variceal bleeding

## Indications for primary prophylaxis
This chapter addresses primary prophylaxis in patients with esophageal varices (EV) and recommendations for the management of gastric varices is discussed in Chap. IX (gastric varices). Choice of treatment for primary prophylaxis 2. Patients with small EVs with risk factors (red spot signs and/or with decompensated cirrhosis Child-Pugh class B or C) should receive NSBBs since they reduce the risk of bleeding in this setting. (A1) 3. Patients with small EV without risk factors should also receive NSBBs prophylaxis, since NSBBs may reduce the incidence of variceal bleeding in this setting. (C1) 4. If monitoring of HVPG is available, treatment with NSBBs should be preferred, since achieving a hemodynamic response defines an excellent long-term prognosis [bib_ref] Hemodynamic response to Carvedilol is maintained for long periods and leads to..., Kirnake [/bib_ref]. (B1) 5. Hemodynamic response to NSBBs is defined as a reduction in HVPG  12 mm Hg or at least 10% from baseline. This is not only associated with a lower risk of first variceal bleeding but also with a lower incidence of ascites and death [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Development of ascites in compensated cirrhosis with severe portal hypertension treated with..., Hernandez-Gea [/bib_ref] [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. (A1) 6. The lack of access to HVPG measurement should not prevent physicians from using NSBBs for primary prophylaxis, since bleeding rates in primary prophylaxis are low even in hemodynamic nonresponders to NSBBs. (B1)
7. Propranolol or carvedilol should be used for prophylactic pharmacological treatment of patients with varices. Carvedilol is more effective than propranolol in primary prophylaxis of variceal bleeding [bib_ref] Randomized comparison of long-term carvedilol and propranolol administration in the treatment of..., Banares [/bib_ref] [bib_ref] Carvedilol or propranolol in portal hypertension? A randomized comparison, Hobolth [/bib_ref]. (B1) 8. In patients with contraindications to NSBBs therapy, NSBBs intolerance, non-adherence to NSBBs or non-responders to NSBBs, EVL should be used.
Endoscopic treatment [bib_ref] Beta-blockers to prevent gastroesophageal varices in patients with cirrhosis, Groszmann [/bib_ref]. Use of EVL in primary prophylaxis should be performed in 2-6-week intervals until variceal eradication. A first follow-up endoscopy after variceal eradication should be performed after 6 months and then every 12 months. If EVL must be restarted the intervals are similar to first EVL [bib_ref] A randomized control trial of bi-monthly versusbi-weekly endoscopicvariceal ligation of esophageal varices, Yoshida [/bib_ref]. (B1)

## Pharmacological treatment with nsbbs
10. There is no need for follow-up endoscopy in patients on pharmacological therapy. (B1) 11. The initial dose of propranolol is 20-40 mg twice daily with a maximum dosage of 160 mg/day in patients without and 80 mg/day with ascites. The initial dose of carvedilol is 6.25 mg once daily with a maximum dosage of 12.5 mg/day [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. (B1) 12. The dose of NSBBs should be increased to achieve a resting heart rate of 55-60 beats per minute (bpm). The systolic blood pressure should not decrease below 90 mm Hg. (B1) 13. There is no relationship between reduction in portal pressure or protection from variceal bleeding and the reduction in resting heart rate or in blood pressure. There is no consensus on whether NSBBs treatment should be continued in patients without a hemodynamic response to NSBBs treatment; however, the benefit of NSBBs treatment may go beyond the portal pressure reducing effect and may also reduce the incidence of ascites, infections, decompensation and death [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Development of ascites in compensated cirrhosis with severe portal hypertension treated with..., Hernandez-Gea [/bib_ref]. (B1) 14. In patients with severe or refractory ascites NSBBs should be discontinued during spontaneous bacterial peritonitis (SBP), a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/l or in the presence of acute kidney injury [bib_ref] Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients..., Mandorfer [/bib_ref] [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. (C2) 15. Isosorbide mononitrate (ISMN) (alone or combined with NSBBs) is not recommended for primary prophylaxis, since it is not more effective in preventing first bleeding but increases side effects [bib_ref] Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis, Angelico [/bib_ref] [bib_ref] Isosorbide mononitrate in the prevention of first variceal bleed in patients who..., Garcia-Pagan [/bib_ref]. (B1) 16. The combination of endoscopic treatment and NSBBs treatment does not further decrease the incidence of bleeding or death but is associated K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S137 with a higher number of side effects and cannot be recommended for primary prophylaxis [bib_ref] Endoscopic variceal ligation plus propranolol versus endoscopic variceal ligation alone in primary..., Sarin [/bib_ref]. (A1) 17. The presence of varices does not represent an indication for proton pump inhibitors (PPIs); however, a short course of PPI post-variceal ligation reduces ulcer size and early bleeding risk [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref] [bib_ref] Proton pump inhibitor therapy is associated with reduction of early bleeding riskafter..., Kang [/bib_ref]. (C1) 18. Transjugular intrahepatic portosystemic shunt (TIPS) placement is not recommended for prevention of first variceal hemorrhage [bib_ref] The treatment of portal hypertension: A meta-analytic review, D&apos;amico [/bib_ref]. (C1)

## V. acute variceal bleeding
The Billroth-III algorithm for treatment of acute variceal bleeding is summarized in Definition 1. Acute variceal bleeding (AVB) is diagnosed in cases of: (a) active bleeding at endoscopy or (b) signs of upper GI bleeding (hematemesis, blood or coagulated blood, melena) in patients with varices in the absence of any other source of bleeding.

## Blood products
2. Blood volume restitution should be done conservatively using packed red cells to maintain a Hb level of 7-8 g/dl (unless comorbidities/active bleeding necessitate more aggressive substitution), and substitution of fluids to maintain hemodynamic stability [bib_ref] Transfusion strategies for acute upper gastrointestinal bleeding, Villanueva [/bib_ref] Antibiotic prophylaxis [bib_ref] Liver stiffness plus platelet count can be used to exclude high-risk oesophageal..., Ding [/bib_ref]. Antibiotic prophylaxis is an integral part of the therapy of variceal bleeding and should be started at admission with i. v. broad spectrum antibiotics which can be de-escalated according to culture results. In the absence of overt infections and successful control of AVB, antibiotic prophylaxis can be stopped after 5-7 days [bib_ref] Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with..., Bernard [/bib_ref]. Prognosis [bib_ref] Isosorbide mononitrate in the prevention of first variceal bleed in patients who..., Garcia-Pagan [/bib_ref]. Active bleeding at endoscopy (under vasoactive therapy) is a poor prognostic sign regarding successful control of bleeding for the short-term period after variceal bleeding [bib_ref] A predictive model for failure to control bleeding during acute variceal haemorrhage, Ben-Ari [/bib_ref]. (B1)
25. An HVPG of 20 mm Hg, active bleeding at endoscopy and a Child-Pugh class C are associated with an increased failure to control bleeding and early mortality [bib_ref] Prognostic value of early measurements of portal pressure in acute variceal bleeding, Moitinho [/bib_ref]. (B1)
Failure to control bleeding [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref] (C1) 11. EVL to prevent rebleeding in secondary prophylaxis should be continued at 2-4-week intervals until eradication of varices (small residual varices can be tolerated) and should then be repeated after 6 months and 12 months. If EVL must be restarted the intervals are similar to the first EVL. 12. Patients with advanced stage liver disease should be evaluated for liver transplantation. In these patients, endoscopic and/or medicinal therapy should be continued until liver transplantation. (C2) 13. EVL is the therapy of choice for variceal rebleeding (or insufficient decrease in HVPG on NSBBs), although EVL may have only moderate beneficial effects especially in these patients (B2). 14. TIPS is indicated in patients with failure of secondary prophylaxis and should be preferred over surgical shunts. (B1) 15. BRTO and surgical devasculariziation are a rescue therapy in patients with failure of secondary prophylaxis with NSBBs and EVL combination therapy if neither a TIPS nor shunt surgery is feasible.
16. TIPS should be considered for secondary prophylaxis in patients with severe/refractory concomitant ascites and/or in patients with NSBBs intolerance or non-response. (C1) 17. In patients with severe or refractory ascites NSBBs should be discontinued during SBP, a decline of systolic blood pressure <90 mm Hg or hyponatremia Na < 125 mmol/L or in cases of acute kidney injury (AKI).

## Vii. measurement of hepatic venous pressure gradient (hvpg)
1. Portal pressure, assessed by the hepatic venous pressure gradient (HVPG) drives the development of liver-related complications and mortality in patients with (compensated) advanced chronic liver disease (cACLD) [bib_ref] Measurement of portal pressure, Abraldes [/bib_ref] [bib_ref] Cirrhosis and portal hypertension: The importance of risk stratification, the role of..., Mura [/bib_ref]. (A1) 2. HVPG measurements are indicated for assessing the prognosis and monitoring the response to etiologic and HVPG-lowering treatment [bib_ref] Measurement of portal pressure, Abraldes [/bib_ref] [bib_ref] Cirrhosis and portal hypertension: The importance of risk stratification, the role of..., Mura [/bib_ref]. (A2) 3. The number needed to treat (NNT) for NSBBs for preventing variceal bleeding ranges from 5 (secondary prophylaxis) to 10 (primary prophylaxis) [bib_ref] Pharmacological treatment of portal hypertension: An evidence-based approach, D&apos;amico [/bib_ref] , underlining the need for methods to assess the expected benefits of NSBBs treatment in the individual patient. (B2) 4. HVPG response is the only established surrogate for the effectiveness of NSBBs in preventing (recurrent) variceal bleeding. If HVPG decreases to a value of <12 mm Hg or is reduced by 20% during NSBBs treatment, patients are protected from variceal bleeding and survival is increased [bib_ref] Hemodynamic events in a prospective randomized trial of propranolol versus placebo in..., Groszmann [/bib_ref] [bib_ref] Relation between portal pressure response to pharmacotherapy and risk of recurrent variceal..., Feu [/bib_ref].
(A1) 5. The assessment of acute HVPG response to intravenous propranolol (0.15 mg/kg given as 15 min infusion) provides a valuable alternative to chronic response assessment (separate measurements). An HVPG reduction by >10% or to <12 mm Hg (measured after the 15 min infusion) is sufficient in the acute setting [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref] [bib_ref] Prognostic value of acute hemodynamic response to i. v. propranolol in patients..., Mura [/bib_ref]. (A1) 6. Several studies support the use of HVPG-guided therapy. Thus, in centers with sufficient experience, HVPG response should be assessed to guide treatment decisions [bib_ref] A Randomized trial to assess whether portal pressure guided therapy to prevent..., Villanueva [/bib_ref] [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref] [bib_ref] Hemodynamic response-guided therapy for prevention of variceal rebleeding: an uncontrolled pilot study, Gonzalez [/bib_ref] [bib_ref] Clinical trial: A randomized controlled study on prevention of variceal rebleeding comparing..., Villanueva [/bib_ref] [bib_ref] Early identification of haemodynamic response to pharmacotherapy is essential for primary prophylaxis..., Sharma [/bib_ref] [bib_ref] Prevention of Rebleeding from esophageal Varices in patients with cirrhosis receiving small-diameter..., Sauerbruch [/bib_ref]. (A2) 7. HVPG measurements should be performed in fasting conditions. Since the procedure is generally well tolerated [bib_ref] A prospective observational study on tolerance and satisfaction to hepatic haemodynamic procedures, Casu [/bib_ref] , ideally no sedation, or if necessary only low doses of midazolam (maximum 0.02 mg/kg) should be used [bib_ref] Low-dose midazolam sedation: An option for patients undergoing serial hepatic venous pressure..., Steinlauf [/bib_ref] [bib_ref] Impact of deep sedation on the accuracy of hepatic and portal venous..., Reverter [/bib_ref]. (A1) 8. HVPG measurements should be performed using a balloon catheter ensuring a sufficient wedge position and in order to maximize the assessed amount of liver parenchyma [bib_ref] Comparison of balloon vs. straight catheter for the measurement of portal hypertension, Zipprich [/bib_ref] [bib_ref] Prospective study comparing different indirect methods to measure portal pressure, Maleux [/bib_ref] [bib_ref] Evaluation of a new balloon occlusion catheter specifically designed for measurement of..., Ferlitsch [/bib_ref]. (A1) 9. Free hepatic venous pressure (FHVP) should be measured in a liver vein 2 cm from the inferior vena cava (stable values are usually obtained after 15 s) [bib_ref] The prognostic value of hepatic venous pressure gradient in patients with cirrhosis..., Silva-Junior [/bib_ref]. A difference between the inferior vena S140 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)

## Viii. portal hypertensive gastropathy
1. Portal hypertensive gastropathy (PHG) is defined as a macroscopically visible mosaic-like pattern of the gastric mucosa (usually fundus or corpus) and can be found in 35-80% of cirrhotic patients, correlates with the Child-Pugh score and the degree of portal hypertension (PHT) [bib_ref] Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural..., Gjeorgjievski [/bib_ref]. A summary for the management of PHT is shown in . (A1) 2. PHG should be differentiated into mild PHG (without signs of bleeding) and severe PHG (red marks or active bleeding). (A1) 3. Gastric antral vascular ectasia (GAVE) is a distinct entity that is endoscopically characterized by tortuous columns of erythematous (mild) or hemorrhagic (severe) lesions in a "watermelon" or diffuse pattern (in the latter case histology may help to confirm diagnosis). GAVE may be present without cirrhosis and is associated with PHT in only 30% of cases [bib_ref] Review article: The management of portal hypertensive gastropathy and gastric antral vascular..., Patwardhan [/bib_ref]. (A1)
4. The incidence of acute PHG bleeding is 2-20% (mostly in severe PHG) [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B2) 5. The incidence of chronic PHG bleeding is around 3-26% and is defined by a >2 g/dl decrease in Hb or by the presence of anemia together with positive faecal occult blood tests [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B2) 6. If PHG is associated with iron deficiency anemia, iron substitution and in severe cases (Hb < 7 g/dL) transfusion should be considered. (B1) 7. There is no evidence for PHG screening or primary bleeding prophylaxis, yet the use of NSBBs for other indications is not discouraged. (C2) 8. Acute bleeding should be pharmacologically treated as AVB. Emergency gastroscopy should rule out other causes for GI bleeding and help to manage endoscopically treatable bleeding [bib_ref] Portal hypertensive gastropathy with a focus on management, Snyder [/bib_ref] [bib_ref] Portal hypertensive gastropathy and colopathy, Urrunaga [/bib_ref]. (A1) 9. PHG with chronic bleeding should be treated with NSBBs [bib_ref] Portal hypertensive gastropathy: A systematic review of the pathophysiology, clinical presentation, natural..., Gjeorgjievski [/bib_ref] [bib_ref] Non-variceal gastrointestinal bleeding inpatientswithliver cirrhosis: A review, Kalafateli [/bib_ref]. (B1) 10. In cases of refractory PHG bleeding TIPS, shunt surgery, argon-plasma coagulation (APC) or even liver transplantation represent rescue therapies. (B2) 11. GAVE bleeding should be treated by APC or Nd:YAG laser coagulation but multiple treatment sessions might be necessary [bib_ref] Diagnosis and management of gastric antral vascular ectasia, Fuccio [/bib_ref]. (A1) 12. In severe or treatment resistant GAVE, band ligation, cryotherapy, radiofrequency ablation or surgical antrectomy represent potential salvage therapies [bib_ref] Diagnosis and management of gastric antral vascular ectasia, Fuccio [/bib_ref]. Acute variceal bleeding from gastric varices [bib_ref] Prevalence, classification and natural history of gastric varices: A long-term follow-up study..., Sarin [/bib_ref]. Initial management of patients with acute variceal bleeding from gastric varices is similar to bleeding from EVs, including vasoactive drugs, restrictive transfusion policy and antibiotic prophylaxis. (B1) 9. Cyanoacrylate glue injection is the treatment of choice for acute variceal bleeding from cardiofundal varices (GOV2, IGV1) and may be also used for GOV1 and IGV2 [bib_ref] Management of gastric varices, Garcia-Pagan [/bib_ref]. (A1) 10. A single injection should consist of maximum 1.0 ml of a cyanoacrylate/lipiodol mixture (1:1)

## X. management of ascites
30% of patients with compensated cirrhosis develop ascites within 5 years of follow-up [bib_ref] Compensated cirrhosis: natural history and prognostic factors, Gines [/bib_ref]. Occurrence of ascites significantly impairs prognosis of liver cirrhosis, with a mortality of 15-20% within 1 year and 44% within 5 years [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D&apos;amico [/bib_ref] [bib_ref] Natural history of patients hospitalized for management of cirrhotic ascites, Planas [/bib_ref]. Treatment of ascites has not yet resulted in significant improvements in survival; however, treating ascites is important because it improves the quality of life of cirrhotic patients and the occurrence of SBP is unlikely in patients without ascites. Important definitions, grading and treatment are summarized in [fig_ref] Table 2: Diagnosis and therapy of ascitesNSAIDs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers,... [/fig_ref].

## Diagnostic approach in patients with ascites
1. Ascites should be graded according to the International Ascites Club guidelines into uncomplicated (grade 1: only visible on ultrasound, grade 2: moderate ascites, grade 3: massive ascites), and refractory ascites (not responsive or intolerant to diuretic therapy even after paracentesis). (A1) 2. Diagnostic paracentesis is indicated in (i) all cirrhotic patients presenting with ascites for the first time, (ii) cirrhotic patients with ascites with unscheduled admission to hospital regardless of the reason, and (iii) cirrhotic patients with ascites with signs of clinical deterioration (such as fever, hepatic encephalopathy, leucocytosis, abdominal pain, upper gastrointestinal bleeding or deterioration in renal function). Substitution of coagulation factors or platelets is not indicated even in patients with severe coagulopathy, because paracentesis rarely leads to serious bleeding complications [bib_ref] Paracentesis of ascitic fluid. A safe procedure, Runyon [/bib_ref]. (B1) 3. Investigation of ascites should include at least determination of ascitic neutrophil count, protein concentration, and the serum-ascites albumin gradient (SAAG). Uncomplicated ascites due to portal hypertension is expected to show a neutrophil count <250/l, a SAAG >1.1 g/dl [bib_ref] The serum-ascites albumin gradient is superior to the exudate-transudate concept in the..., Runyon [/bib_ref] and a protein level <2.5 g/dl. The SAAG is calculated by subtracting the ascitic fluid albumin level from the serum albumin level (both determined on the same day). (B1) 4. Additionally, aerobic and anaerobic blood culture bottles should be inoculated with ascitic fluid for bacteriological diagnosis of SBP or bacterascites (neutrophil count <250/l but positive ascites fluid culture). (B1) Therapy of uncomplicated ascites [bib_ref] Noninvasive tools and risk of clinically significant portal hypertension and varices in..., Abraldes [/bib_ref]. Initial therapy of patients with cirrhosis and ascites consists of moderate sodium restriction (90 mmol NaCl/day, corresponding to 5.2 g NaCl/day), and diuretic therapy. Sodium restriction to less than 5 g NaCl/day is not recommended due to the risk of aggravating malnutrition that is usually present in these patients [bib_ref] Protein-calorie malnutrition in liver cirrhosis, Lautz [/bib_ref]. (B1) 6. Diuretic therapy should be started with spironolactone 100 mg and furosemide 40 mg [bib_ref] Diuresis in the ascitic patient: A randomized controlled trial of three regimens, Fogel [/bib_ref] [bib_ref] Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis:..., Angeli [/bib_ref]. In the case of insufficient ascites control or lack of effectiveness, doses of spironolactone and furosemide can be increased by 100 mg and 40 mg every 3-5 days. The daily dose of 400 mg spironolactone and 160 mg furosemide should not be exceeded. (A1) 7. Furosemide should not be administered intravenously as a bolus in cirrhotic patients because of risk of deterioration in the glomerular filtration rate (GFR) [bib_ref] Immediate effects of furosemide on renal hemodynamics in chronic liver disease with..., Daskalopoulos [/bib_ref]. (B1) 8. The use of spironolactone or amiloride as single agents or combined with thiazides may have a role for outpatients or previously untreated patients due to a lesser need for dose adjustments [bib_ref] Spironolactone alone or in combination with furosemide in the treatment of moderate..., Santos [/bib_ref] [bib_ref] Optimum use of diuretics in managing ascites in patients with cirrhosis, Bernardi [/bib_ref] (B1) 9. Eplerenone is an alternative for men with gynecomastia, but has not been compared to spironolactone or furosemide in the setting of portal hypertensive ascites [bib_ref] Eplerenone reversesspironolactone-inducedpainful gynaecomastiain cirrhotics, Dimitriadis [/bib_ref]. 100 mg of spironolactone is considered equivalent to 50 mg of eplerenone. Furthermore, amiloride as single agent or combined with thiazides may have a role in patients who are intolerant or develop side effects to spironolactone or furosemide [bib_ref] Randomized clinical study of the efficacy of amiloride and potassium canrenoate in..., Angeli [/bib_ref]. (B2) 10. Vaptans are not beneficial for the long-term management of portal hypertensive ascites [bib_ref] Satavaptan for the management of ascites in cirrhosis: Efficacy and safety across..., Wong [/bib_ref]. (A1) 11. Rapid weight loss during diuretic therapy might increase the risk of hypovolemia, AKI and hepatic encephalopathy and thus, weight loss during diuretic therapy should not exceed 1 kg/day or 4 kg/ week. (B2) 12. In patients with tense ascites (grade 3), paracentesis is the treatment of choice and should be followed by diuretic therapy. Total paracentesis should be carried out as a single procedure, even when a large volume of ascites is present, as long as it is hemodynamically tolerated by the patient. (B1) 13. Plasma volume expansion using albumin is recommended in all patients undergoing paracentesis if more than 5 l of ascites have been removed, for prevention of hypovolemia and circulatory dysfunction [bib_ref] Albumin infusion in patients undergoing large-volume paracentesis: A meta-analysis of randomized trials, Bernardi [/bib_ref]. Albumin at a dose of 8 g/l of ascites removed should be administered (i. e. 100ml 20% albumin per 2.5 l ascites removed). Removal of less than 5 l does not appear to have hemodynamic consequences. (A1) K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S143 original article [bib_ref] Acute hemodynamic response to beta-blockers and prediction of long-term outcome in primary..., Villanueva [/bib_ref]. Patients responsive to diuretics should primarily be treated with sodium restriction and diuretics and should not undergo serial paracentesis. (B1) 15. In cirrhotic patients with severe hyponatremia (plasma sodium levels <125 mmol/l) fluid restriction is recommended since the underlying pathophysiology is usually dilutional/hypervolemic hyponatremia. (A1) [bib_ref] Carvedilol for primary prophylaxis of variceal bleeding in cirrhotic patients with haemodynamic..., Reiberger [/bib_ref]. In severe hyponatremia diuretics should be stopped, since at these levels diuretics are ineffective and worsen hyponatremia. Substitution with concentrated NaCl solutions should be avoided [bib_ref] Severe symptomatic hyponatremia: treatment and outcome. A study of 64 cases, Sterns [/bib_ref].
(C2) 17. If hyponatremia occurs together with hepatic encephalopathy or with AKI, plasma volume expansion with saline and/or albumin should be considered. (C2) 18. Patients with moderate to severe ascites should be evaluated for liver transplantation. (B1) 19. The administration of non-steroidal anti-inflammatory drugs (NSAIDs) in patients with decompensated cirrhosis and ascites can lead to renal failure and therefore should be avoided [bib_ref] Effect of indomethacin and prostaglandin A1 on renal function and plasma renin..., Boyer [/bib_ref]. The same is true for angiotensin receptor blockers and angiotensin converting enzyme inhibitors [bib_ref] Acute effects of captopril on systemic and renal hemodynamics and on renal..., Pariente [/bib_ref] [bib_ref] Effects of low-dose captopril on renal hemodynamics and function in patients with..., Gentilini [/bib_ref]. Aminoglycosides should only be used in cases where infections cannot be otherwise treated [bib_ref] Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional..., Cabrera [/bib_ref] [bib_ref] Risk factors forthedevelopmentofrenaldysfunctioninhospitalizedpatients with cirrhosis, Hampel [/bib_ref]. (A1) 20. In the absence of strong indications, proton pump inhibitors (PPIs) should not be used in patients with ascites since PPIs might be associated with a higher risk of infections [bib_ref] Long-term use of antibiotics and proton pump inhibitors predict development of infections..., O&apos;leary [/bib_ref]. (A2) 21. Ascites per se is not a contraindication for NSBBs, but they should be used with caution. Carvedilol should not be used in patients with severe or refractory ascites due to induction of hypotension [bib_ref] Beta-blockersinpatients with cirrhosis and ascites: Type of beta-blocker matters, Njeib [/bib_ref]. In patients with severe or refractory ascites, high doses of propranolol (>80 mg/day) should be avoided [bib_ref] Betaadrenergicblockadeanddecompensated cirrhosis, Reibergert [/bib_ref]. (C2)

## Refractory ascites
Only less than 10% of patients with cirrhosis and ascites are refractory to treatment regimens consisting of sodium restriction and oral diuretics [bib_ref] Peritoneovenous shunting as compared with medical treatment in patients with alcoholic cirrhosis..., Stanley [/bib_ref].

## Refractory ascites is defined by the international ascites club [70] (a1):
-as ascites that cannot be mobilized by intensive diuretic therapy (up to a maximum of 400 mg spironolactone and 160 mg furosemide per day) and confirmed dietary sodium restriction (diuretic-resistant ascites), -or as ascites that rapidly reaccumulates after therapeutic paracentesis (within 4 weeks), -or as the situation, where the maximum dose of diuretics cannot be administered due to side effects, such as electrolyte imbalance, renal fail-ure, and encephalopathy (diuretic-intolerant ascites). 23. Refractory ascites can develop secondary to hepatocellular carcinoma or portal vein thrombosis; therefore, ultrasound examination should be performed to exclude these complications of cirrhosis. (B1) 24. A characteristic feature of refractory ascites is impaired urinary sodium excretion despite maximum tolerated doses of diuretics [bib_ref] Management of cirrhosis and ascites, Gines [/bib_ref]. Since urine collection for 24 h is cumbersome, a spot urinary sodium/potassium ratio <2.5 is a reasonable surrogate for diuretic-resistant ascites [bib_ref] Spot urinary sodium for assessing dietary sodium restriction in cirrhotic ascites, El-Bokl [/bib_ref]. Diuretic treatment should be continued only when urinary sodium excretion under diuretic therapy is greater than 30 mmol/day. (B2) 25. Due to the poor prognosis of patients with refractory ascites liver transplantation must be considered. (A1) [bib_ref] Use of proton pump inhibitors in the management of gastroesophageal varices: A..., Lo [/bib_ref]. Patients with refractory ascites should be evaluated for TIPS, since TIPS is associated with improved survival [bib_ref] Transjugular intrahepatic portosystemic shunt for refractory ascites: A meta-analysis of individual patient..., Salerno [/bib_ref] [bib_ref] Survival benefit of TIPS versus serial paracentesis in patients with refractory ascites:..., Gaba [/bib_ref] [bib_ref] Association between Transjugular Intrahepatic Portosystemic shunt and survival in patients with cirrhosis, Berry [/bib_ref]. (A1) 27. If TIPS is contraindicated or refused by the patient, repetitive large volume paracentesis in combination with albumin substitution, sodium restriction and diuretic therapy should be performed. (B1) 28. The efficacy and safety of low-flow pump systems to remove ascites from the peritoneal cavity into the bladder in patients with refractory ascites remains to be established [bib_ref] Automated low flow pump system for the treatment of refractory ascites: A..., Bellotp [/bib_ref] [bib_ref] Automated low-flow ascites pump for the treatment of cirrhotic patients with refractory..., Stirnimann [/bib_ref]. (C2) 29. In patients with severe/refractory ascites NSBBs should be discontinued during SBP [bib_ref] Nonselective beta blockers increase risk for hepatorenal syndrome and death in patients..., Mandorfer [/bib_ref] , a decline of systolic blood pressure <90 mmHg, hyponatremia <125 mmol/L or in the presence of AKI.
Hepatic hydrothorax [bib_ref] Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with..., Bernard [/bib_ref]. Hepatic hydrothorax represents a (usually a rightsided) pleural effusion in patients with cirrhosis and ascites in the absence of any other pleural or pulmonary disease [bib_ref] Hepatic hydrothorax: Clinical features,management,andoutcomesin77patientsandreview of the literature, Badillo [/bib_ref]. (A1) 31. Diagnostic pleuracentesis of hepatic hydrothorax should be performed at first diagnosis and include similar testing as for ascitic fluid. (B1) 32. The absolute neutrophil count is usually higher than in the ascitic fluid and thus, the diagnosis of bacterial infection of the pleural effusion should mainly be based on culture results [bib_ref] Spontaneous bacterial empyema in cirrhotic patients: Analysis of eleven cases, Xiol [/bib_ref]. (C2) 33. Hepatic hydrothorax should be primarily treated with salt restriction and diuretics [bib_ref] Evidence-based review of the management of hepatic hydrothorax, Singh [/bib_ref]. (B1) 34. TIPS should be considered for recurrent hepatic hydrothorax not responsive to diuretic therapy [bib_ref] Treatment of refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt: Longterm results..., Siegerstetter [/bib_ref] [bib_ref] Safety and efficacy of transjugular intrahepatic portosystemic shunt creation for the treatment..., Spencer [/bib_ref]. (B1) 35. Other treatment modalities including pleurodesis [bib_ref] Effectiveness and safety of Pleurodesis for hepatic Hydrothorax: A systematic review and..., Hou [/bib_ref] or permanent drainage systems [bib_ref] Outcome analysis of cirrhotic patients undergoing chest tube placement, Liu [/bib_ref] cannot be recommended for treatment of hepatic S144 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III)
K original article hydrothorax. The role of novel indwelling pleural catheters is not yet clear [bib_ref] Indwelling tunneled pleural catheters for the management of hepatic Hydrothorax. A pilot..., Chen [/bib_ref]. (B2) 36. Patients with recurrent hepatic hydrothorax should be evaluated for liver transplantation [bib_ref] Liver transplantation in patients with hepatic hydrothorax, Xiol [/bib_ref]. (A1)

## Xi. spontaneous bacterial peritonitis (sbp)
1. All patients presenting with ascites for the first time, with recurrence of ascites, or deterioration of ascites, evidence of systemic infection, GI bleeding, worsening liver or renal function, or hepatic encephalopathy should undergo paracentesis to screen for SBP. (A1) 2. Ascitic fluid and blood cultures should be performed using blood culture bottles. Even in culture-negative SBP, positive blood cultures might hint at the responsible organism. (A1) 3. In patients with an ascitic fluid absolute neutrophil count >250/l or a positive ascitic fluid culture, antibiotic therapy with gram-negative coverage (e. g. aminopenicillin/beta-lactamase inhibitor, third generation cephalosporin, or quinolone) should be started immediately. (A1) 4. Chinolones should not be used to treat SBP in patients who were on norfloxacin prophylaxis. (B1) 5. In selected high-risk patients (e. g. nosocomial SBP as defined by onset of signs and symptoms of infection after 72 h from hospitalization and/or patients with sepsis), the use of combination regimens as initial therapy might be warranted [bib_ref] The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a..., Piano [/bib_ref]. (A2) 6. To prevent the development of hepatorenal syndrome (HRS) type of AKI, 1.5 g/kg bodyweight albumin should be administered in patients with SBP at the time of diagnosis, plus 1 g/kg body weight on day three [bib_ref] Effect of intravenous albumin on renal impairment and mortality in patients with..., Sort [/bib_ref]. (A1) 7. Blood pressure should be carefully monitored in patients with SBP and NSBBs should be discontinued in the case of systolic blood pressure <90 mm Hg, hyponatremia Na < 125 mmol/L, or AKI [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. (C2) 8. In the case of an ascitic fluid neutrophil count <250/L but clinical evidence of infection, similar antibiotic therapy should be initiated and continued until culture results are available. (B1) 9. A second paracentesis should be performed 48 h after initiation of the antibiotic therapy to demonstrate a decrease of the ascitic absolute neutrophil count by 25% of the initial value [bib_ref] Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial..., Fong [/bib_ref]. (A1) 10. A smaller drop is highly suggestive of failure of the antibiotic regimen. In these patients, antibiotic therapy should be adopted based on culture results and susceptibility testing. (A1) 11. If culture-negative, antibiotic therapy should be changed to cover gaps in the antibacterial spectrum of the initial therapy, as well as relevant multidrug-resistant gram-negative and gram-positive bacteria (e. g. meropenem plus daptomycin) [bib_ref] The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a..., Piano [/bib_ref]. (B1) 12. Due to the poor prognosis of patients who recovered from SBP, liver transplantation should be considered in these patients. (A1) 13. All patients with a history of SPB should be treated continuously with secondary prophylaxis using norfloxacin 400 mg/day or alternatively co-trimoxazole (800 mg/160 mg/day). (A1) 14. Given the inevitable risk of antibiotic resistance, the use of prophylactic antibiotics in patients without a history of SBP should be restricted to patients at high risk for SBP: low ascites protein (<15 g/l) with advanced liver failure (Child-Pugh score 9 points with serum bilirubin 3 mg/dL) or impaired renal function (serum creatinine sCr  1.2 mg/dL, blood urea nitrogen 25 mg/dl, or serum sodium 130 mmol/L) [bib_ref] Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival..., Fernandez [/bib_ref] [bib_ref] Antibiotic prophylaxis in cirrhosis: Good and bad, Fernandez [/bib_ref]. (C1) 15. In patients with Child-Pugh C10-15 norfloxacin prophylaxis seems to decrease 6-months mortality. (B1)16. Based on the currently available evidence, rifaximin cannot be used as a substitute for norfloxacin/co-trimoxazole [bib_ref] The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis..., Hanouneh [/bib_ref] [bib_ref] Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic..., Vlachogiannakos [/bib_ref] [bib_ref] Impact of rifaximin on the frequency and characteristics of spontaneous bacterial peritonitis..., Lutz [/bib_ref] [bib_ref] Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for..., Assem [/bib_ref] [bib_ref] Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial..., Elfert [/bib_ref] [bib_ref] Rifaximin has no effect on hemodynamics in decompensated cirrhosis: A randomized, double-blind,..., Kimer [/bib_ref].

## Xii. management of acute kidney injury and hepatorenal syndrome (hrs-aki)
Acute kidney injury (AKI) is a common complication of cirrhosis with a significant prognostic impact [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis, Arroyo [/bib_ref] [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref]. As a consequence of systemic and splanchnic arterial vasodilatation, renal perfusion is critical in patients with advanced cirrhosis and CSPH [bib_ref] Recent advances in our understanding of hepatorenal syndrome, Wong [/bib_ref]. AKI is commonly triggered by precipitating events leading to further circulatory compromise including overdose of diuretics, large volume paracentesis without albumin replacement, GI blood loss, and infections (e. g. SBP) [bib_ref] Liver cirrhosis and kidney, Gerbes [/bib_ref].

## Diagnosis and definitions
The traditional diagnostic criteria of renal failure in cirrhosis (percentage increase in sCr, 50% to a final value 1.5 mg/dl) [bib_ref] Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis, Salerno [/bib_ref] were replaced by the Kidney Disease Improving Global Outcome (KDIGO) criteria to diagnose AKIand adapted for patients with cirrhosis by the International Club of Ascites (ICA) in 2015 [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. One of the main modifications of the ICA-AKI criteria is the abandonment of a threshold of sCr  K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S145 - Continuous infusion (initial dose 0.5 mg/h; max. studied in RCTs 3 mg/hour) - Complete response is defined by a decrease in sCr to a value within 0.3 mg/dL of the baseline value. - Partial response is defined by a regression of at least one AKI stage - The vasoconstrictor dose should be increased if there is no response after 3 days of treatment - In non-responders, treatment should be discontinued after 14 days

## Other considerations for hrs-aki
- RRT should be restricted to patients eligible for liver transplantation - TIPS should be considered in patients with severe/refractory ascites - Patients with HRS-AKI associated with SBP should receive secondary antibiotic prophylaxis - Patients should be evaluated for liver transplantation Normal renal 1.5 mg/dl to diagnose AKI in cirrhosis, since smaller rises in sCr have also been shown to have a negative prognostic impact in these patients [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref] [bib_ref] New diagnostic criteria and management of acute kidney injury, Wong [/bib_ref].
A detailed algorithm for diagnosis and treatment of AKI in patients with cirrhosis is shown in .

## Diagnosis and definitions
1. AKI in cirrhosis should be diagnosed according to the ICA-AKI criteria [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (B1): -Increase in sCr  0.3 mg/dl within 48 h or -Increase in sCr  50% from a baseline value that is known or presumed to have occurred in the past 7 days.
-A baseline sCr value obtained in the previous 3 months should be used. If no previous sCr value is available, the sCr on admission should be used.
In cases of impairment of renal function (sCr  1.5 mg/dl) at time of admission and a clearly identifiable precipitating event, it is reasonable to assume AKI based on clinical judgement. -The use of a reduction in urine output as part of the diagnostic criteria was eliminated in the new ICA criteria for the diagnosis of AKI because many patients with cirrhosis and ascites are oliguric as part of the sodium and water retention syndrome and yet maintain a nearly normal GFR [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by..., Angeli [/bib_ref]. Based on that only the changes in sCr should be S146 Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) K original article used to diagnose AKI in patients with cirrhosis (B1). 2. AKI in cirrhosis should be staged according to the ICA-AKI criteria [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] : (B1) -ICA-AKI stage 1: increase in sCr  0.3 mg/dl or 1.5 to 2-fold from baseline -ICA-AKI stage 2: increase in sCr > 2 to 3-fold from baseline -ICA-AKI stage 3: increase in sCr > 3-fold from baseline or 4 mg/dl with an acute increase 0.3 mg/dl or need for renal replacement therapy (RRT) 3. The hepatorenal syndrome type of AKI (HRS-AKI, formerly known as HRS type 1) is defined as  stage 2 ICA-AKI fulfilling all other diagnostic criteria of HRS-AKI [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] : (A1) -Presence of ascites -No improvement in sCr after 2 consecutive days of withdrawal of diuretics and plasma volume expansion with albumin (1 g/kg, max.100 g/day) -Absence of shock -Exclusion of nephrotoxic agents (e. g. NSAIDs, aminoglycosides, contrast media) -Exclusion of parenchymal kidney disease (proteinuria <500 mg/day, <50 red blood cells per high power field, normal renal ultrasound) 4. Hepatorenal syndrome type 2 is defined as slowly progressive impairment of renal function (sCr > 1.5 mg/dl) [bib_ref] Working Party proposal for a revised classification system of renal dysfunction in..., Wong [/bib_ref] [bib_ref] The evolving concept of acute kidney injury in patients with cirrhosis, Wong [/bib_ref] fulfilling the abovementioned diagnostic criteria of HRS-AKI and is usually associated with refractory ascites [bib_ref] Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis, Arroyo [/bib_ref] [bib_ref] New consensus definition of acute kidney injury accurately predicts 30-day mortality in..., Wong [/bib_ref] (A1).

## Management of aki and hrs-aki in cirrhosis
The initial management of AKI should focus on identification and correction of precipitating factors that further exaggerate the already disturbed hemodynamics in advanced cirrhosis [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Acutekidneyinjuryinlivercirrhosis: Newdefinition andapplication, Wongf [/bib_ref] [bib_ref] Diagnosing and treating renal disease in cirrhotic patients, Wong [/bib_ref].
5. The following measures should be taken in cirrhotic patients with initial ICA-AKI stage 1. (A1) -Review of all medications (including over the counter drugs) -Reduction or withdrawal of diuretic therapy and/ or lactulose for patients who are volume-depleted from diuretics or excess lactulose use -Withdrawal of all potentially nephrotoxic agents (e. g. NSAIDs) -Careful assessment of ongoing use of drugs potentially inducing/aggravating hypotension (e. g. NSBBs) [bib_ref] Betaadrenergicblockadeanddecompensated cirrhosis, Reibergert [/bib_ref] [bib_ref] Interferon-free regimens improve portal hypertension and histological necroinflammation in HIV/HCV patients with..., Schwabl [/bib_ref] -Plasma volume expansion with crystalloids or albumin in patients with clinically suspected hypovolemia -Blood transfusion in patients with AKI after GI blood loss -Screening for bacterial infections (e. g. SBP) and early or empiric antibiotic treatment if an infection is diagnosed or strongly suspected [bib_ref] Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis, Arabi [/bib_ref] 6. In the case of response (return of sCr to a value within 0.3 mg/dl of the baseline value), patients should be followed closely for early identification of potential new episodes of AKI [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref] [bib_ref] Acute kidney injury in decompensated cirrhosis, Tsien [/bib_ref]. (B2) -Assessment of sCr every 2-4 days during hospitalization -Assessment of sCr every 2-4 weeks during the first 6 months after discharge 7. In the case of stage 2 or 3 ICA-AKI or progression of stage 1 ICA-AKI to a higher stage, patients need to be assessed for the presence of HRS-AKI in addition to the following measures [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (B1): -Administration of the same general measures as described for patients with ICA-AKI stage 1, -Withdrawal of diuretics if not withdrawn already, -Plasma volume expansion with albumin for two consecutive days (1 g/kg body weight, maximum 100 g/day).

## Treatment of hrs-aki
8. Patients with HRS-AKI should be treated with vasoconstrictors (terlipressin or norepinephrine) in combination with albumin (40 g/day) [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (A1). 9. Patients with ICA-AKI stage 1 and sCr < 1.5 mg/dl fulfilling the diagnostic criteria of HRS-AKI can be treated the same way on a case-by-case basis [bib_ref] Diagnosis and management of acute kidney injury in patients with cirrhosis: Revised..., Angeli [/bib_ref]. (C2). 10. Patients with HRS type 2 can be treated similarly [bib_ref] Terlipressin and albumin vs albumin in patients with cirrhosis and hepatorenal syndrome:..., Martin-Llahi [/bib_ref] [bib_ref] Renal failure in cirrhotic patients: Role of terlipressin in clinical approach to..., Alessandria [/bib_ref] [bib_ref] Treatment of type 2 hepatorenal syndrome in patients awaiting transplantation: Effects on..., Rodriguez [/bib_ref]. (A1). original article [bib_ref] Randomized comparison of long-term carvedilol and propranolol administration in the treatment of..., Banares [/bib_ref]. Patients should be monitored for hyponatremia, which more commonly occurs in patients with less advanced liver disease and (near) normal baseline serum sodium levels [bib_ref] Hyponatremia in patients treated with terlipressin for severe gastrointestinal bleeding due to..., Sola [/bib_ref]. (A1). 18. Continuous infusion (initial dose of 2 mg/day; maximum 12 mg/day) decreases the rate of adverse events, the mean effective terlipressin dose and, thus, might also decrease costs as compared to bolus administration (initial dose of 0.5 mg every 4 h; maximum 2 mg every 4 h). Continuous infusion might be preferred over bolus administration [bib_ref] Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment..., Cavallin [/bib_ref]. (A1) 19. Although terlipressin has been consistently shown to improve renal function, its impact on survival is less clear. (A1) 20. Terlipressin is particularly beneficial in patients with systemic inflammatory response or sepsis and might also prevent variceal bleeding during the period of discontinuation of NSBBs [bib_ref] Arandomizedtrialcomparingterlipressin and noradrenaline in patients with cirrhosis and septic shock, Choudhury [/bib_ref]. (B2) Norepinephrine 21. Norepinephrine (initial dose of 0.5 mg/h; maximum dose studied in RCTs: 3 mg/h) is an equally effective and inexpensive alternative to terlipressin [bib_ref] Terlipressin versus noradrenaline in the treatment of hepatorenal syndrome: Systematic review with..., Mattos [/bib_ref].

## (a1)
Response to treatment and considerations for follow-up [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. Complete response to treatment is defined by a decrease in sCr to a value within 0.3 mg/dl of the baseline value, while a regression of at least one AKI stage is considered as partial response. (B1) [bib_ref] Isosorbide-5-mononitrate versus propranolol in the prevention of first bleeding in cirrhosis, Angelico [/bib_ref] [bib_ref] Natural history and prognostic indicators of survival in cirrhosis: A systematic review..., D&apos;amico [/bib_ref]. Patients with acute PVT should receive anticoagulation for at least 6 months to prevent extension to mesenteric veins and intestinal ischemia and in order to achieve recanalization [bib_ref] Acuteportal vein thrombosis unrelated to cirrhosis: A prospective multicenter followup study, Plessier [/bib_ref] [bib_ref] Portal vein thrombosis, Chawla [/bib_ref]. (A1) 5. For acute PVT, LMWH should be initiated and shifted to oral anticoagulation after stabilization of the patient. (A1) 6. In symptomatic patients with acute, non-cirrhotic PVT (i. e. ascites and/or risk of intestinal infarction) a TIPS combined with local clot fragmentation/aspiration should be considered [bib_ref] Ascites in patients with noncirrhotic nonmalignant extrahepatic portal vein thrombosis, Spaander [/bib_ref]. (B1) 7. Lifelong anticoagulation should be given to PVT patients with a permanent prothrombotic condition. (A1) 8. Long-term anticoagulation is also recommended in patients without identifcation of (prothrombotic) risk factor or thrombus extension into the mesenteric/splenic vein. Malignant PVT (regardless of cirrhotic/non-cirrhotic PVT) [bib_ref] A randomized control trial of bi-monthly versusbi-weekly endoscopicvariceal ligation of esophageal varices, Yoshida [/bib_ref]. In general, anticoagulation is not indicated for malignant PVT. (C2) 20. Anticoagulation may be considered for symptomatic and progressive malignant PVT. (C1) 21. TIPS should not be used for treatment of malignant PVT. (C1)
Acute cirrhotic, non-malignant PVT [bib_ref] Beta adrenergic blockade and decompensated cirrhosis, Reiberger [/bib_ref]. Anticoagulation is indicated in cirrhotic patients with acute PVT with progression to mesenteric/ splenic vein or signs of intestinal ischemia. (A1) 23. Anticoagulation should be considered in all candidates for liver transplantation with PVT [bib_ref] Splanchnic vein thrombosis in candidates for liver transplantation: Usefulness of screening and..., Francoz [/bib_ref].
(B1) 24. Anticoagulation may also be used in non-candidates for liver transplantation with progressive PVT or with persisting prothrombotic conditions [bib_ref] Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management..., Senzolo [/bib_ref] [bib_ref] Splanchnic vein thrombosis in candidates for liver transplantation: Usefulness of screening and..., Francoz [/bib_ref] [bib_ref] Natural course of extrahepatic nonmalignant partial portal veinthrombosisinpatientswithcirrhosis, Luca [/bib_ref] [bib_ref] Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: A pilot study, Santis [/bib_ref] [bib_ref] Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: Role of..., Amitrano [/bib_ref] [bib_ref] Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis:..., Nery [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (C1) 25. No recommendations regarding type of anticoagulation treatment can be made for cirrhotic PVT; however, LMWH and VKA appear to be equally effective for cirrhotic, non-malignant PVT [bib_ref] Prospective evaluation of anticoagulation and transjugular intrahepatic portosystemic shunt for the management..., Senzolo [/bib_ref] [bib_ref] Systemic thrombolysis of portal vein thrombosis in cirrhotic patients: A pilot study, Santis [/bib_ref] [bib_ref] Portal vein thrombosis after variceal endoscopic sclerotherapy in cirrhotic patients: Role of..., Amitrano [/bib_ref] [bib_ref] Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis:..., Nery [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (B1) 26. LMWH should be used as a fixed or weight-adjusted dose. Anti-Xa monitoring of LMWH is not representative in patients with cirrhosis [bib_ref] Increased anticoagulant response to low-molecular-weight heparin in plasma from patients with advanced..., Senzolo [/bib_ref]. (C2) 27. VKA should be monitored in patients with cirrhosis with an INR aimed at 2-3. (C1) 28. Before starting anticoagulation in patients with cirrhotic PVT bleeding prophylaxis should be implemented. (C1) 29. Patients with low platelet count (<50 G/L) are at higher risk of bleeding complications under anticoagulation [bib_ref] Expanding consensus in portal hypertension: Report of the Baveno VI consensus workshop:..., De Franchis [/bib_ref] [bib_ref] Efficacy and safety of anticoagulation on patients with cirrhosis and portal vein..., Delgadomg [/bib_ref]. (B2) 30. Recent data suggest that DOACs can be safely used in patients with compensated cirrhosis [bib_ref] Direct oral anticoagulants in cirrhosis patients pose similar risks of bleeding when..., Intagliata [/bib_ref].
[fig] Figure 1: Flow chart for screening of varices in cirrhotic patients. TE transient elastography, PLT platelet count, GOV gastroesophageal varices II. Diagnosis and screening of portal hypertension [/fig]
[fig] Vasoconstrictor treatment 11: Patients receiving vasoconstrictors should be preferably treated in an intermediate care (IMCU) or intensive care unit (ICU). (B1) 12. Vasoconstrictors should be preferably administered via a central venous line under continuous blood pressure and electrocardiography (ECG) monitoring. (B1) 13. Non-availability of an IMCU/ICU should, however, not defer the use of vasoconstrictors in patients with HRS-AKI. (B1) Terlipressin 14. Terlipressin is the most intensively studied vasoconstrictor for the treatment of HRS-AKI. (A1) 15. A bolus of terlipressin induces a statistically significant reduction in portal pressure over 3-4 h and also increases mean arterial pressure [145]. (A1). 16. Terlipressin should be used with caution in patients with cardiovascular disease, since it may induce ischemia. (A1)K Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III) S147 [/fig]
[table] Table 2: Diagnosis and therapy of ascitesNSAIDs, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, aminoglycosides, carvedilol, propranolol with caution (not more than 80 mg/day) NSAIDs non-steroidal anti-inflammatory drugs, TIPS transjugular intrahepatic portosystemic shunt, OLT orthotopic liver transplantation in order to minimize the risk of embolization; however, more than one single injection is usually needed to obtain sufficient obliteration[65]. (B2) 11. Endoscopic variceal sclerotherapy is not recommended for treatment of acute or prophylactic treatment of gastric varices. (B1) 12. EVL is not an established therapy for bleeding GOV2, IGV1 + IGV2 due to a higher rebleeding rate compared to cyanoacrylate, EVL may only be per-Linton-Nachlas balloon tamponade can be used as a bridge to hemostatic therapy in cases of failure to control bleeding from cardiofundal varices; however, risk of rebleeding after deflation is high. (B2) 15. BRTO represents an additional treatment option for bleeding cardiofundal varices. (B2) 16. Rarely surgical shunts, surgical devascularization (plus splenectomy), or splenic embolization are needed as rescue therapy for bleeding gastric varices not responding to vasoactive and endoscopic therapy if a TIPS cannot be performed. (C2) [/table]