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Diagnostic paracentesis in new- onset ascites 1.1. A diagnostic paracentesis is recommended in all patients with new-onset ascites. ( Quality of evidence: moderate; Recommendation: strong ) 1.2. The initial ascitic fluid analysis should include total protein concentration and calculation of the serum ascites albumin gradient (SAAG). ( Quality of evidence: moderate; Recommendation: strong ) 1.3. Ascites fluid analysis for cytology, amylase, brain natriuretic peptide (BNP) and adenosine deaminase should be considered based on pretest probability of specific diagnosis ( Quality of evidence: moderate; Recommendation: weak ) 2.1. Diagnostic paracentesis should be carried out without a delay to rule out spontaneous bacterial peritonitis SBP) in all cirrhotic patients with ascites on hospital admission. ( Quality of evidence: moderate; Recommendation: strong ) 2.2. A diagnostic paracentesis should be performed in patients with GI bleeding, shock, fever or other signs of systemic inflammation, gastrointestinal symptoms, hepatic encephalopathy, and in patients with worsening liver or renal function. ( Quality of evidence: moderate; Recommendation: strong )

2.3. Ascitic neutrophil >250/mm 3 count remains the gold standard for the diagnosis of SBP and this can be performed either by manual microscopy or using automated counts, based on flow cytometry for counting and differentiating cells. ( Quality of evidence: moderate; Recommendation: strong ) 2.4. Ascitic fluid culture with bedside inoculation of blood culture bottles should be performed to guide the choice of antibiotic treatment when SBP is suspected. ( Quality of evidence: moderate; Recommendation: strong ) 2.5. Immediate empirical antibiotic therapy should be determined with due consideration of context of SBP (community acquired or healthcare associated), severity of infection and local bacterial resistance profile. Cefotaxime has been widely studied, but choice of antibiotic should be guided by local resistance patterns and protocol. ( Quality of evidence: moderate; Recommendation: strong ) 2.6. A second diagnostic paracentesis at 48 hours from the start of treatment to check the efficacy of antibiotic therapy should be considered in those who have apparently inadequate response or where secondary bacterial peritonitis is suspected. ( Quality of evidence: low; Recommendation: weak )

2.7. Patients presenting with gastrointestinal bleeding and underlying ascites due to cirrhosis should receive prophylactic antibiotic treatment (cefotaxime has been widely studied but the antibiotic should be chosen based on local data) to prevent the development of SBP. ( Quality of evidence: strong; Recommendation: strong ) 2.8. Patients who have recovered from an episode of SBP should be considered for treatment with norfloxacin (400 mg once daily), ciprofloxacin (500 mg once daily, orally) or co-trimoxazole (800 mg sulfamethoxazole and 160 mg trimethoprim daily, orally) to prevent further episode of SBP. ( Quality of evidence: low; Recommendation: weak ) 2.9. Primary prophylaxis should be offered to patients considered at high risk, as defined by an ascitic protein count <1.5 g/dL. However, it is important that the potential risks and benefits and existing uncertainties are communicated to patients. ( Quality of evidence: low; Recommendation: weak ) 3.1. Patients with cirrhosis and ascites should have a moderately salt restricted diet with daily salt intake of no more than 5–6.5 g (87–113 mmol sodium). This translates to a no added salt diet with avoidance of precooked meals. ( Quality of evidence: moderate; Recommendation: strong )

3.2. Patients with cirrhosis and ascites should receive nutritional counselling on the sodium content in the diet. ( Quality of evidence: weak; Recommendation: strong ) 4.1. In patients with the first presentation of moderate ascites, spironolactone monotherapy (starting dose 100 mg, increased to 400 mg) is reasonable. In those with recurrent severe ascites, and if faster diuresis is needed (for example, if the patient is hospitalised), combination therapy with spironolactone (starting dose 100 mg, increased to 400 mg) and furosemide (starting dose 40 mg, increased to 160 mg) is recommended. ( Quality of evidence: moderate; Recommendation: strong ) 4.2. All patients initiating diuretics should be monitored for adverse events. Almost half of those with adverse events require diuretic discontinuation or dose reduction. ( Quality of evidence: low; Recommendation: weak ) 4.3. Hypovolaemic hyponatraemia during diuretic therapy should be managed by discontinuation of diuretics and expansion of plasma volume with normal saline. ( Quality of evidence: low; Recommendation: weak ) 4.4. Fluid restriction to 1–1.5 L/day should be reserved for those who are clinically hypervolaemic with severe hyponatraemia (serum sodium <125 mmol/L). ( Quality of evidence: low; Recommendation: weak )

4.5. Hypertonic sodium chloride (3%) administration should be reserved for those who are severely symptomatic with acute hyponatraemia. Serum sodium should be slowly corrected. (Quality of evidence: low; Recommendation: weak) 4.6. It may be appropriate to consider use of midodrine in refractory ascites on a case by case basis. ( Quality of evidence: low; Recommendation: weak ) 5.1. Patients should give informed consent for a therapeutic or diagnostic paracentesis. ( Quality of evidence: low; Recommendation: strong ) 5.2. Ultrasound guidance should be considered when available during LVP to reduce the risk of adverse events ( Quality of evidence: low; Recommendation: weak ) 5.3. Routine measurement of the prothrombin time and platelet count before therapeutic or diagnostic paracentesis and infusion of blood products are not recommended. ( Quality of evidence: moderate; Recommendation: strong ) 6.1. Albumin (as 20% or 25% solution) should be infused after paracentesis of >5 L is completed at a dose of 8 g albumin/L of ascites removed. ( Quality of evidence: high; Recommendation: strong ) 6.2. Albumin (as 20% or 25% solution) can be considered after paracentesis of <5 L at a dose of 8 g albumin/L of ascites removed in patients with ACLF or high risk of post-paracentesis acute kidney injury. ( Quality of evidence: low; Recommendation: weak )

6.3. In patients with SBP and an increased serum creatinine or a rising serum creatinine, infusion of 1.5 g albumin/kg within 6 hours of diagnosis, followed by 1 g/kg on day 3, is recommended. ( Quality of evidence: low; Recommendation: weak ) Transjugular intrahepatic portosystemic shunt (TIPSS) 7.1. TIPSS should be considered in patients with refractory ascites. ( Quality of evidence: high; Recommendation: strong ) 7.2. Caution is required if considering TIPSS in patients with age >70 years, serum bilirubin >50 µmol/L, platelet count <75×10 9 /L, model for end-stage liver disease (MELD) score ≥18, current hepatic encephalopathy, active infection or hepatorenal syndrome. ( Quality of evidence: moderate; Recommendation: strong ) 8.1. Suitability and timing of surgical repair of umbilical hernia should be considered in discussion with the patient and multidisciplinary team involving physicians, surgeons and anaesthetists. ( Quality of evidence: low; Recommendation: strong ) 9.1. TIPSS should be considered in patients with HH after discussion with the multidisciplinary team. ( Quality of evidence: low; Recommendation: strong ) 9.2. In patients with HH who are not undergoing a TIPSS and/or a liver transplant evaluation, alternative palliative interventions should be considered. ( Quality of evidence: low; Recommendation: strong ) Non-selective beta-blockers (NSBB) and ascites

10.1. Refractory ascites should not be viewed as a contraindication to NSBB. ( Quality of evidence: moderate; Recommendation: strong ) 10.2. Patients with refractory ascites who are taking NSBB should be monitored closely, and dose reduction or discontinuation may be appropriate in those who develop hypotension or acute/progressive renal dysfunction. ( Quality of evidence: moderate; Recommendation: strong ) 11.1. An automated low-flow ascites pump should be considered only in special circumstances with robust arrangements of clinical governance, audit or research. ( Quality of evidence: low; Recommendation: weak ) 12.1. Patients with refractory ascites who are not undergoing evaluation for liver transplant should be offered a palliative care referral. Besides repeated LVP, alternative palliative interventions for refractory ascites should also be considered. ( Quality of evidence: weak; Recommendation: strong ) 13.1. Randomised controlled trials (RCT) with large sample size should evaluate the role of antibiotics in the secondary prophylaxis for SBP in ascites secondary to cirrhosis. 13.2. Large RCTs should assess the role of midodrine in the management of ascites. 13.3. Cost-effectiveness of long-term administration of albumin to patients with decompensated cirrhosis and ascites should be evaluated. 13.4. Role of nutritional interventions in the management of ascites should be evaluated.

13.5. Large RCT of long-term carvedilol versus no carvedilol in patients with refractory ascites without large oesophageal varices should be carried out. 13.6. Role of TIPSS in the management of hepatic hydrothorax should be compared with other therapeutic interventions. 13.7. The cost-effectiveness and the effect of automated low-flow ascites pumps on the quality of life of patients with refractory ascites should be evaluated. 13.8. Effectiveness and safety of long-term abdominal drains should be assessed in RCTs for the palliative care of patients with cirrhosis and refractory ascites.

These guidelines have been produced on behalf of the British Society of Gastroenterology (BSG) in collaboration with the British Association for the Study of the Liver (BASL). These guidelines are aimed at healthcare professionals who look after patients with cirrhosis and ascites. Ascites is the build-up of fluid in the belly (abdomen). This occurs when the liver gets irreversibly scarred, a condition known as cirrhosis. Ascites is the most common complication of cirrhosis. All patients with a new onset of ascites should have the fluid tested. This involves inserting a small needle into the abdomen and removing about two tablespoons of ascitic fluid. The fluid is then analysed for protein and white cell count. Protein count can help differentiate whether the cause of ascites is cirrhosis or whether the ascites is due to other causes like heart disease or cancer. The white cell count indicates whether there is an infection in the ascitic fluid. If infection is present, this is treated with a short course of antibiotics. Infection of ascites should be ruled out at every hospital admission as it carries a high risk of death and should therefore be diagnosed and treated promptly. After this initial treatment, patients are given long-term antibiotics to prevent repeat infections.

No salt should be added at the table to food. The total amount of salt in food per day should not be more than the equivalent of one teaspoon. Patients should read labels on prepared foods to confirm their daily salt intake is within the limit of 5 g of salt. The initial treatment for patients with ascites involves taking medication, commonly known as 'water tablets' (diuretics). These drugs are begun at a small dose, which is gradually increased until the ascites is treated. Diuretics can have side effects such dehydration, confusion, abnormal levels of sodium and potassium and kidney damage. Therefore patients should be monitored while taking these tablets. As the liver disease progresses the ascites may no longer respond to medication. This is known as untreatable or refractory ascites. This requires the patient to come into hospital every few weeks to have a temporary drain inserted into the abdomen and the ascitic fluid drained. If more than 5 L of fluid is removed, patients are also given a protein solution into the vein to prevent dehydration.

In patients with untreatable ascites, alternatives to repeated hospital drainage include placing a small tube (stent) in the liver. This specialised procedure is known as a transjugular intrahepatic portosystemic shunt (TIPSS). The TIPSS procedure is effective in reducing the need for repeated fluid drainage. Because of potential side effects, patients should be selected carefully for this procedure. This is particularly true for patients with more advanced liver disease, where the insertion of a TIPSS can potentially be harmful. The only curative option for untreatable ascites is liver transplantation. If the patient is not suitable for liver transplantation, medical care then focuses on controlling the ascites symptoms. This is known as palliative care. The most common palliative treatment for untreatable ascites is repeated hospital drainage. Alternative treatments for untreatable ascites, such as long-term abdominal drains, need further research.

Contemporary data from an NHS hospital serving a population of 700 000, found 164 adults with a new diagnosis of ascites over a period of 5 years. Of these, 55% had cirrhosis (alcohol-related liver disease 58, non-alcoholic fatty liver disease 21, chronic viral hepatitis 4, autoimmune liver diseases 3 and cryptogenic cirrhosis 4), 29% had malignancies (gynaecological 12, gastrointestinal 25 and others 11), 6% cardiac failure (CF), 3% end-stage renal disease (ESRD) and 7% other aetiologies. Development of ascites is an important milestone in the natural history of cirrhosis. About 20% of patients with cirrhosis have ascites at their first presentation, and 20% of those presenting with ascites die in the first year of the diagnosis. The aim of this guideline is to review and summarise the evidence that guides clinical diagnosis and management of ascites in patients with cirrhosis.

A detailed description of the pathogenesis of ascites formation is beyond the scope of this article, but two key factors involved in the pathogenesis of ascites formation are portal hypertension and retention of sodium and water. This is summarised in . An elevated sinusoidal pressure is essential for the development of ascites, as fluid accumulation does not develop at portal pressure gradient below 8 mm Hg, and rising corrected sinusoidal pressure correlates with decreased 24-hour urinary excretion of sodium. Architectural changes associated with advanced fibrosis are clearly the primary mechanism underlying increased intrahepatic resistance to the portal flow in cirrhosis. In addition, phenotypic changes in hepatic stellate cells and liver sinusoidal endothelial cells contribute to the pathophysiology. Activated stellate cells become contractile, and their recruitment around newly formed sinusoidal vessels increases the vascular resistance. Reduction in the production/bioavailability of nitric oxide (NO) in the cirrhotic liver adds further to the rise in vascular tone. Overall, vasoconstriction has been estimated to account for about 25% of the increased resistance within the liver.

Increased portal pressure is sensed by intestinal microvasculature that generates angiogenic factors such as vascular endothelial growth factor, and these stimulate the development of portosystemic collaterals through the opening of pre-existing vessels or new vessel formation. When the portal pressure rises further, induction of endothelial nitric oxide synthase and over production of NO leads to splanchnic arterial vasodilatation. This, in turn, increases portal blood flow, thus exacerbating portal hypertension. Portosystemic collaterals also permit vasodilators such as NO, prostacyclin and endocannabinoids to enter the systemic circulation leading to a state of ‘effective hypovolaemia’. This activates sympathetic nervous system stimulating reabsorption of sodium in proximal, distal tubules, loop of Henle and collecting duct as well as the renin–angiotensin–aldosterone system, leading to sodium absorption from distal tubule and collecting duct. Renal sodium retention and eventual free water clearance due to non-osmotic release of arginine–vasopressin and its action on V2 receptor in the collecting duct underlie the fluid retention associated with oedema and ascites in cirrhosis.

More recently, it has been hypothesised that bacterial translocation associated with portal hypertension in cirrhosis and related pathogen-associated, molecular pattern activated innate immune responses lead to systemic inflammation. This is associated with vasodilatation as well as release of proinflammatory cytokines, reactive oxygen and nitrogen species, contributing to organ dysfunction.

Ascites that is not infected and which is not associated with the development of the hepatorenal syndrome (HRS). Ascites can be graded as mild when ascites is detectable only by ultrasound examination, moderate when it causes moderate symmetrical distension of the abdomen and large when it causes marked abdominal distension.

Ascites that cannot be mobilised or the early recurrence of which (ie, after therapeutic paracentesis) cannot be satisfactorily prevented by medical treatment. This includes two different subgroups.

Clinical evaluation should include history of exposure to risk factors for cirrhosis and physical examination to look for evidence to support chronic liver disease or an alternative diagnosis. Shifting dullness is detectable when about one and a half litres of free fluid accumulate in the abdomen; the physical sign has 83% sensitivity and 56% specificity in detecting ascites. However, in the presence of obesity or smaller amount of fluid, imaging such as ultrasound or CT is necessary to confirm the presence of ascites.

Aspiration of ascitic fluid and its laboratory analysis is an essential step in the management of patients with newly diagnosed ascites. In cirrhosis, hepatic sinusoids are less permeable owing to fibrous tissue deposition, resulting in ascites with low protein content. It is important to estimate total protein level in ascites fluid; a concentration below 1.5 g/dL (or 15 g/L) is a risk factor for the development of spontaneous bacterial peritonitis. In addition, serum ascites albumin gradient (SAAG) should be estimated routinely. A cut-off point of 1.1 g/dL (or 11 g/L) differentiates between causes of ascites with high sensitivity, although alternative causes should be considered based on the clinical scenario (). Hepatic sinusoids are normally permeable in heart failure, which allows for leakage of protein-rich lymph into the abdominal cavity and therefore, total protein concentration in ascitic fluid is high (>2.5 g/dL) in combination with a high SAAG. In such a situation, measurement of brain natriuretic peptide (BNP) in the serum±ascites is useful. Total protein concentrations >2.5 g/dL within the ascites and serum BNP >364 ng/L are suggestive of underlying or additional cardiac disease, whereas serum protein values <182 ng/L rule out cardiac disease.

In low SAAG states, clinical context and imaging should guide the investigational approach. The yield for positive cytology in the context of malignancy is variable, ranging from 0% to 96.7%, in part determined by the site of the tumour. Combining cytology with tumour markers in the ascitic fluid may increase the positive predictive value (PPV), specifically the use of carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM), CA 15-3 and CA 19-9. However, CA 125 in the serum or ascites has no role as a discriminator and will commonly be elevated by the presence of ascites from any cause. Where peritoneal TB is considered plausible, ascites can be sent for acid-fast bacilli smear and culture, although culture positivity occurs in <50% and smear-positive ascites is rare. Adenosine deaminase is more useful to distinguish between peritoneal TB and carcinomatosis, with an area under the receiver operating characteristic curve of 0.98; adenosine deaminase levels of <40 IU/mL are used to exclude TB.

Pancreatic ascites is a rare complication of pancreatitis, although more common when a pseudocyst is present. In pancreatic ascites, the amylase level in the ascitic fluid is typically >1000 IU/L or greater than six times the serum amylase, with mean values exceeding 4000 IU/L in a recent cohort of 80 patients. Raised polymorphonuclear leucocytes (PMN) count may also be found in pancreatic ascites. The ascitic fluid samples required from the diagnostic paracentesis is summarised in .

A diagnostic paracentesis is recommended in all patients with new-onset ascites. ( Quality of evidence: moderate; Recommendation: strong ) The initial ascitic fluid analysis should include total protein concentration and calculation of SAAG. ( Quality of evidence: moderate; Recommendation: strong ) Ascites fluid analysis for cytology, amylase, BNP and adenosine deaminase should be considered based on pretest probability of specific diagnosis ( Quality of evidence: moderate; Recommendation: weak )

Spontaneous bacterial peritonitis is the development of bacterial infection of ascites in the absence of any intra-abdominal surgically treatable source of infection. The prevalence of SBP in outpatients is 1.5–3.5% and approximately 10% in hospitalised patients. A recent European study detected a prevalence of 11.3% among inpatients. When first described, mortality associated with SBP exceeded 90%, but, in-hospital mortality has been reduced to approximately 20% with early diagnosis and prompt treatment. In an observational study, each hour of delay in diagnostic paracentesis after admission was associated with a 3.3% increase of in-hospital mortality after adjusting for model for end-stage liver disease (MELD) score. Long-term survival remains poor; 1-year survival after hospitalisation with SBP in a UK study was found to be 34%. Patients recovering from an episode of SBP should always be considered as potential candidates for liver transplantation if they have not already been assessed.

The diagnosis of SBP is confirmed when ascitic neutrophil count is >250 cells/mm 3 in the absence of an intra-abdominal and surgically treatable source of sepsis. A cut-off point of 250 neutrophils/mm 3 has the greatest sensitivity, although a cut-off point of 500 neutrophils/mm 3 has greater specificity. A meta-analysis of primary data from 14 prospective trials has defined the positive and negative likelihood ratios of SBP at different thresholds for total white cell count (WCC) and PMN in ascitic fluid. WCC >1000 cells/µL or PMN ≥500 cells/µL are most accurate and yield positive likelihood ratios of 9.1 (95% CI 5.5 to 15.1) and 10.6 (95% CI 6.1 to 18.3), respectively. Likelihood ratios for WCC >500 cells/µL (5.9; 95% CI 2.3 to 15.5) and PMN >250 cells/µL (6.4; 95% CI 4.6 to 8.8) support routine clinical practice of using lower thresholds, where the greater risk lies with underdiagnosing SBP.

Historically, ascitic neutrophil counts have been performed by manual microscopy, but, this is time and cost intensive. Automated counts, based on flow cytometry for counting and differentiating cells, are now used in most centres. This technique has been shown to have sensitivity and specificity close to 100%, allowing a tube containing ethylenediamine tetra-acetate (EDTA; as used for plasma full blood count) to be inoculated with ascitic fluid and processed on a standard blood count analyser. Reagent strips have insufficient sensitivity for reliable use in this context and hence cannot be recommended to replace cell count to diagnose SBP.