PREAMBLE
Purpose of the revision
Liver cirrhosis is a progressive condition accompanied by a wide range of complications. Among these, ascites and ascites-related complications are frequently encountered in routine clinical practice, alongside variceal bleeding and hepatic encephalopathy, and they have a substantial impact on patient outcomes. The development of ascites is a well-recognized indicator of disease progression and poor prognosis. Following the onset of ascites, the 1-year and 2-year survival rates of patients with decompensated cirrhosis decline to approximately 60% and 45%, respectively, underscoring the critical importance of timely diagnosis and appropriate therapeutic intervention. Since the 2017 revision of the Korean Association for the Study of the Liver (KASL) Clinical Practice Guidelines for liver cirrhosis focusing on ascites and related complications, progress has been made in the areas of diagnosis, treatment, clinical management, and prognostic assessment. Notable changes in the clinical environment include evolving patterns of antimicrobial resistance, the emergence of new evidence and strategies for nutritional management, and a growing emphasis on improving the safety of ultrasound-guided procedures. In addition, substantial advances have been made in recent years, such as expansions in the therapeutic applications of albumin, growing evidence of the clinical utility of transjugular intrahepatic portosystemic shunt (TIPS), and increasing calls to revise the international consensus criteria for the diagnosis of acute kidney injury (AKI).
These developments have had a meaningful influence on treatment strategies for patients with liver cirrhosis, necessitating revision of clinical practice guidelines to reflect current evidence. Accordingly, the Clinical Practice Guideline Revision Committee for Ascites-Related Complications in Liver Cirrhosis of the Korean Association for the Study of the Liver conducted systematic reviews of the latest literature and developed updated recommendations that integrate international trends with real-world clinical practice in Korea.
A major distinguishing feature of this revised guideline is the strengthening of evidence-based recommendations through the application of independent systematic literature reviews. Key clinical questions were identified, areas requiring reappraisal of existing evidence were selected and evaluated through structured systematic reviews, and the findings were incorporated into the guideline recommendations.
Through a comprehensive and multidimensional analysis of both domestic and international literature, the most up-to-date evidence regarding treatment efficacy, diagnostic accuracy, and safety outcomes was quantitatively assessed. Based on this evidence, the levels of evidence and the strength of recommendations were clearly determined in accordance with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework. In addition, for each subsection, areas in which current evidence remains insufficient to support definitive clinical recommendations were explicitly described at the end of each section. Topics requiring further investigation and future research directions were also highlighted.
Key directions of this revision
This revision was undertaken to reflect recent shifts in evidence-based clinical practice. Findings derived from independent systematic literature reviews were incorporated. The principal directions of this revision are summarized below.
Strengthening the evidence base for the role and clinical utility of albumin
Recent randomized controlled trials and meta-analyses have demonstrated that albumin confers benefits beyond simple plasma volume expansion. These benefits include antioxidant and anti-inflammatory effects, improvement of endothelial function, and stabilization of systemic hemodynamics. Collectively, these effects contribute to a reduction in ascites-related complications and improved clinical outcomes. In this guideline revision, the physiological roles and therapeutic value of albumin are systematically reviewed, and supporting evidence for its use in diverse clinical settings, including ascites control, infection, and renal impairment, is presented.
Incorporation of updated evidence and strengthened recommendations for TIPS
Historically, TIPS was primarily regarded as a rescue therapy for refractory ascites or variceal bleeding. However, recent studies indicate that TIPS, when performed at an appropriate stage of disease, may contribute to improved survival. In this revision, the usefulness of TIPS in the control of ascites and management of hepatorenal syndrome were re-evaluated through systematic literature review.
Revision of clinical practice guidelines for the diagnosis and management of acute kidney injury in patients with cirrhosis based on revised international criteria
Recently, the Acute Dialysis Quality Initiative–International Club of Ascites (ADQI-ICA) published expert consensus recommendations on the diagnosis and management of AKI. Nevertheless, these recommendations remain under active international discussion and require further validation. Accordingly, these clinical practice guidelines proposed their own diagnostic criteria and therapeutic strategies by integrating recently published evidence with existing recommendations. This approach aims to enhance flexibility in clinical judgment and practical application in real-world settings, while allowing room for future modifications as additional evidence becomes available. In addition, detailed considerations were provided regarding the assessment of the need for renal replacement therapy following early diagnosis, strategies for hemodynamic optimization, and evidence supporting the concomitant use of albumin.
Evidence supporting the safety and clinical relevance of ultrasound-guided paracentesis was also reviewed and confirmed, and the rationale for recommendations regarding prophylactic antibiotic therapy in spontaneous bacterial peritonitis (SBP) was presented. Furthermore, the clinical significance of urinary neutrophil gelatinase–associated lipocalin (NGAL) in AKI associated with cirrhosis was evaluated, and corresponding recommendations were provided.
Systematic literature review
In this revision, systematic literature reviews were conducted in accordance with the principles of evidence-based medicine. The GRADE methodology was applied to assess the quality of evidence and the strength of recommendations.
Target population
These clinical practice guidelines for ascites-related complications in liver cirrhosis are intended for patients with cirrhosis caused by chronic hepatitis B, chronic hepatitis C, metabolic dysfunction–associated steatotic liver disease, alcohol-related liver disease, and other chronic liver diseases, who subsequently develop ascites and related complications.
Intended users
The clinical practice guidelines for ascites-related complications in cirrhosis were developed to provide healthcare professionals caring for patients with chronic liver disease and cirrhosis with structured and comprehensive clinical information for the evaluation and management of ascites-related complications in daily practice. In addition, the guidelines aim to offer practical and clinically relevant guidance for residents and fellows in training, as well as for the educators responsible for their supervision and instruction.
Guideline revision committee, revision process, and funding
The Guideline Revision Committee for Ascites-Related Complications in Liver Cirrhosis was established following a proposal and approval by the Board of Directors of the Korean Association for the Study of the Liver (KASL). The committee consisted of 18 experts in hepatology, primarily board-certified gastroenterologists, as well as specialists from related disciplines. All costs associated with guideline development were supported by the KASL.
Financial support did not influence the independence of the guideline content. Each committee member was responsible for collecting and analyzing evidence in their assigned area and drafting the corresponding manuscript sections and recommendations. When evidence was insufficient to reach clear conclusions, expert opinions from domestic specialists in cirrhosis management were consulted. External experts from the Korean Society of Nephrology, the Korean Society of Interventional Radiology, the Korean Society of Infectious Diseases, the Korean Liver Transplantation Society, and the Korean Society for Parenteral and Enteral Nutrition were also consulted as needed.
Literature search for evidence collection
To develop evidence-based clinical practice guidelines, the committee systematically searched and reviewed relevant domestic and international literature published up to September 2025 using the databases PubMed, MEDLINE, and KoreaMed.
Classification of evidence levels and recommendation grades
The collected literature was analyzed to determine the quality of evidence, which was classified according to a modified GRADE system (
Table 1). Based on study design, randomized controlled trials were initially assigned a high level of evidence, while observational studies were initially assigned a low level of evidence. The certainty of evidence was subsequently upgraded or downgraded according to factors influencing methodological quality. Based on the likelihood that future research may change the estimated effects, the highest level of evidence with minimal likelihood of change was defined as level A, moderate evidence with possible change as level B, and low evidence with a high likelihood of change as level C. The strength of recommendation was also determined using the GRADE framework, taking into account not only the quality of evidence but also the clinical impact, cost, and socio-economic considerations. Recommendations were classified as either strong (1) or weak (2). A strong recommendation indicates that the desirable effects of an intervention clearly outweigh undesirable effects and that the intervention should be applied in most patients. A weak recommendation suggests that the evidence is less certain, and alternative approaches may be appropriate depending on patient values, preferences, and clinical circumstances.
The 2026 Revision Committee of the Clinical Practice Guidelines for Ascites-Related Complications in Cirrhosis identified the following key clinical issues and developed evidence-based statements and recommendations for each topic.
Diagnosis and differential diagnosis of ascites in cirrhosis
Which diagnostic modality is the most sensitive for detecting the presence of ascites?
What is the diagnostic accuracy of using the serum–ascites albumin gradient (SAAG) and ascitic fluid protein concentration obtained via paracentesis?
How should ascites related to cirrhosis be differentiated from ascites due to other causes, such as heart failure, malignant ascites, or tuberculous ascites?
Treatment and dietary management of ascites in cirrhosis
How should ascites in patients with cirrhosis be managed?
What dietary strategies should be recommended for patients with cirrhotic ascites?
Refractory ascites
How should refractory ascites be diagnosed and treated?
Diagnosis and management of hyponatremia associated with cirrhotic ascites
How should hyponatremia associated with ascites in cirrhosis be diagnosed and managed?
Spontaneous bacterial peritonitis
How is spontaneous bacterial peritonitis diagnosed?
How should spontaneous bacterial peritonitis be treated?
How can spontaneous bacterial peritonitis be prevented?
Definition, diagnostic criteria, and pathophysiology of acute kidney injury and hepatorenal syndrome
How should acute kidney injury and hepatorenal syndrome be diagnosed in patients with cirrhosis?
Management of acute kidney injury and hepatorenal syndrome
How should acute kidney injury and hepatorenal syndrome be treated in patients with cirrhosis?
Other ascites-related complications in cirrhosis: hepatic hydrothorax and hernia
How should hepatic hydrothorax in patients with cirrhosis be diagnosed and managed?
How should hernias in patients with cirrhosis be treated?
Considerations for medication use in patients with cirrhosis
What factors should be considered when prescribing medications for patients with cirrhosis?
External review and approval process
Draft manuscripts prepared by individual committee members were reviewed and approved through committee meetings. In addition to content accuracy, guideline quality was evaluated using the Appraisal of Guidelines for Research and Evaluation II instrument. The guidelines were revised and refined based on feedback obtained through an advisory committee composed of 10 experts, including hepatology specialists affiliated with the KASL and experts from external academic societies, as well as through a public hearing that included both professionals and members of the general public. The finalized clinical practice guidelines developed through this process subsequently received final approval from the Board of Directors of the KASL.
Publication and future updates
The 2026 Clinical Practice Guidelines for Ascites-Related Complications in Liver Cirrhosis were officially announced on June 11, 2026, at Liver Week 2026 hosted by the KASL. The Korean version is available on the official website of the association (
https://www.kasl.org), and the English version will be published in
Clinical and Molecular Hepatology. The guidelines will be updated as new evidence becomes available and when revision is deemed necessary to improve patient care and public health.
ASCITES DUE TO LIVER CIRRHOSIS
Diagnosis and differential diagnosis
Medical history
The most common cause of ascites is liver cirrhosis, accounting for approximately 75–85% of cases [
1,
2]. Other causes include malignant ascites, tuberculous peritonitis, heart failure, pancreatitis, and nephrotic syndrome (
Table 2). Therefore, when evaluating a patient with ascites for the first time, clinicians should not only identify the underlying etiology of cirrhosis, such as viral hepatitis or alcohol-related liver disease, but also pay careful attention to differential diagnosis of other conditions.
Physical examination
When ascites is suspected, abdominal percussion may reveal flank dullness, shifting dullness, and a fluid wave. These findings usually become detectable when ascitic volume exceeds approximately 1.5 L. Physical examination may be challenging in obese patients or in those with small-volume ascites; in such cases, imaging studies such as abdominal ultrasonography or computed tomography are helpful. Abdominal ultrasonography can detect as little as 100 mL of ascites [
3]. Ascites is classified as grade 1 when detectable only on imaging, grade 2 when readily identified on physical examination, and grade 3 when presenting as massive or tense ascites. In patients with ascites secondary to heart failure, jugular venous distension may be observed.
Diagnostic paracentesis
Paracentesis is the most rapid and effective method for ascitic fluid analysis [
4] and is essential for differentiating the cause of ascites and diagnosing infection [
5]. Diagnostic paracentesis is mandatory for patients with newly diagnosed grade 2 or higher ascites, those hospitalized for exacerbation of ascites, cases with suspected infection (e.g., fever, abdominal pain), or patients presenting with concomitant cirrhosis-related complications such as variceal hemorrhage, hepatic encephalopathy, or AKI [
6]. In hospitalized patients with cirrhotic ascites, early diagnostic paracentesis performed within 12–24 hours of admission has been associated with significantly lower in-hospital mortality, shorter length of stay, and reduced incidence of AKI compared with delayed paracentesis [
7].
Paracentesis is usually performed in the left or right lower quadrant, with the left lower quadrant often preferred because of a thinner abdominal wall and greater fluid accumulation [
8] Common complications include persistent ascitic fluid leakage, bleeding (abdominal wall hematoma or intraperitoneal hemorrhage), and bowel perforation. In a systematic review and meta-analysis conducted by the guideline committee (131 studies, 12,509 procedures), reported rates were 2.6% for leakage, 0.3–0.7% for bleeding, and 0.2% for gastrointestinal perforation (
Supplementary Material 1). Systemic complications such as hyponatremia and renal dysfunction were also reported. Death related to paracentesis is rare [
9–
14], with an incidence of 0.02% in a study of 4,729 patients [
11].
Paracentesis is absolutely contraindicated in patients with disseminated intravascular coagulation or acute abdomen requiring surgical intervention [
15]. Pregnancy and severe bowel distension are considered relative contraindications [
15]. Ultrasound-guided paracentesis may improve procedural success and reduce complications, but is not mandatory in all cases and should be applied according to clinical judgment [
16,
17]. Coagulopathy or thrombocytopenia does not significantly increase the risk of bleeding and is not an absolute contraindication [
18–
20]. In patients receiving antiplatelet agents such as aspirin or anticoagulants, the overall risk of procedure-related bleeding has been reported to be low, and major radiologic guidelines also classify paracentesis as a low-risk procedure [
21,
22]. However, a case of major bleeding was reported following large-volume paracentesis (LVP) performed shortly after apixaban administration in a patient with concomitant hepatic dysfunction and renal failure [
23]. In the absence of large randomized trials, decisions should be individualized, balancing bleeding risk against thromboembolic risk. In the systematic review and meta-analysis conducted by the Guideline Revision Committee, ultrasound-guided paracentesis was associated with a reduced risk of bleeding (
Supplementary Material 1); therefore, ultrasound guidance may be considered when performing paracentesis in patients at high risk of bleeding.
Ascitic fluid analysis and differential diagnosis
After paracentesis, the gross appearance of ascitic fluid should be assessed. Cloudy fluid suggests infection or malignant ascites; dark brown fluid may indicate biliary perforation; black fluid raises suspicion for pancreatic necrosis or metastatic melanoma. Milky fluid suggests chylous ascites, which occurs due to lymphatic disruption associated with trauma, cirrhosis, or malignancy and is characterized by triglyceride levels ≥200 mg/dL, sometimes exceeding 1,000 mg/dL.
Initial ascitic fluid evaluation should include cell count and differential, albumin, and total protein (
Table 3). Serum albumin should be measured concurrently to calculate the SAAG.
SAAG is particularly useful for distinguishing ascites related to portal hypertension [
4]. A SAAG ≥1.1 g/dL is suggestive of portal hypertension, as seen in liver cirrhosis, cardiac disease, Budd–Chiari syndrome, portal vein thrombosis, sinusoidal obstruction syndrome, and massive liver metastasis, whereas a SAAG <1.1 g/dL suggests conditions such as tuberculous peritonitis or peritoneal carcinomatosis (
Fig. 1). In the systematic review and meta-analysis conducted for this guideline, SAAG demonstrated a pooled sensitivity of 91.7% (95% confidence interval [CI] 87.9–94.4) and specificity of 80.5% (95% CI 71.4–87.2) for predicting portal hypertension (
Supplementary Material 2). When SAAG is ≥1.1 g/dL, ascitic protein concentration further refines the diagnosis: a protein level ≥2.5 g/dL suggests cardiac disease or early Budd–Chiari syndrome, whereas <2.5 g/dL is more consistent with cirrhosis [
24–
26].
In patients undergoing repeated therapeutic paracentesis without changes in clinical status, only cell count and differential are required, and repeated measurement of SAAG or total protein is unnecessary [
27,
28]. When ascitic infection is suspected, ascitic fluid should be promptly collected at bedside and inoculated into aerobic and anaerobic blood culture bottles, which enhances bacterial survival and improves diagnostic yield [
29].
In clinically specific situations, additional diagnostic tests should be performed to identify the underlying cause of ascites (
Table 3). When malignancy is suspected, ascitic fluid cytology and measurement of carcinoembryonic antigen (CEA) can be helpful. Cytological examination is particularly useful for the diagnosis of peritoneal carcinomatosis. Even if malignant cells are not detected on initial examination, repeat cytological analyses should be considered when there is strong clinical suspicion, as repeated testing can substantially increase the diagnostic yield. Indeed, the cumulative sensitivity of cytology has been reported to reach 96.7% after three examinations [
30]. Although CEA has relatively low sensitivity, it demonstrates high specificity; therefore, higher CEA levels strongly suggest malignant ascites [
31]. Tuberculous peritonitis is typically characterized by lymphocyte-predominant ascites; however, definitive diagnosis is often challenging. In such cases, additional tests including acid-fast bacilli smear and culture, as well as measurement of adenosine deaminase, should be performed. When secondary bacterial peritonitis due to bowel perforation or other intra-abdominal pathology is suspected, ascitic fluid glucose and lactate dehydrogenase (LDH) levels should be assessed. Secondary bacterial peritonitis is suggested by an ascitic glucose level below 50 mg/dL and an ascitic LDH level higher than the corresponding serum LDH level [
32]. If pancreatic ascites is suspected, ascitic fluid amylase should be measured, which is typically markedly elevated, often exceeding 1,000 U/L. In rare cases, urinary ascites may develop as a result of traumatic or iatrogenic injury to the bladder or ureter. This condition can be diagnosed based on elevated urea and creatinine levels in the ascitic fluid [
33,
34]. When the etiology of ascites remains unclear despite comprehensive evaluation, a definitive diagnosis can be established through peritoneal biopsy and culture obtained via laparotomy or laparoscopy. Approximately 5% of ascites cases result from the coexistence of two or more underlying causes (
Table 2) [
1]. Mixed ascites is particularly difficult to diagnose and may arise from a combination of conditions such as heart failure, diabetic nephropathy, and liver cirrhosis [
35]. In such cases, each individual condition alone may be insufficient to cause ascites; however, their combined effects lead to sodium and water retention, ultimately resulting in ascites formation.
Areas requiring further research
Evidence remains limited regarding whether ultrasound-guided paracentesis improves mortality rate, length of hospital stay, or healthcare costs beyond reducing procedural complications, and prospective studies are needed. In addition, alternative or adjunctive biomarkers are required for specific ascites subtypes, such as malignant or tuberculous ascites, in which the diagnostic performance of SAAG is limited. Standardized tools to predict paracentesis-induced circulatory dysfunction are lacking, and further research is needed to define the role of point-of-care ultrasonography in ascites diagnosis.
Recommendations
1. Diagnostic paracentesis should be performed in patients with newly diagnosed grade ≥2 ascites, in hospitalized patients with worsening ascites, in those with suspected ascitic infection, and in patients with cirrhosis-related complications. (A1)
2. Initial ascitic fluid analysis should include cell count and differential, albumin, and total protein, and SAAG should be calculated for differential diagnosis. (A1)
3. When ascitic infection is suspected, early paracentesis (within 12–24 hours of admission) with bedside inoculation of ascitic fluid into blood culture bottles is recommended. (A1)
Treatment
General management
Treatment of the underlying liver disease
The cornerstone of ascites management is the treatment of underlying liver disease. Ascites caused by alcohol-related liver disease, chronic viral hepatitis, or autoimmune liver disease can be controlled by appropriate etiologic therapy (
Table 4) [
36]. Alcohol-related liver disease is a major cause of ascites [
37], and abstinence, the cornerstone of treatment, improves hepatic fibrosis and reduces portal hypertension, thus contributing to ascites control [
38]. Alcohol abstinence can lead to resolution of ascites, enhance diuretic responsiveness, and ultimately improve overall survival in patients with cirrhosis. In a study of patients with alcohol-related cirrhosis and Child-Pugh class C, those who maintained abstinence had a 3-year survival rate of approximately 75%, whereas continued alcohol use was significantly associated with increased mortality [
39]. In patients with decompensated cirrhosis due to hepatitis B virus, antiviral therapy using oral nucleos(t)ide analogues has been shown to improve liver function and reduce complications of cirrhosis, including ascites [
36,
40–
43]. Similarly, in a study of 267 patients with decompensated cirrhosis due to hepatitis C virus, 12-week treatment with sofosbuvir and velpatasvir led to improvement in Model for End-stage Liver Disease (MELD) scores in 51% of patients and in Child-Pugh scores in 47% of patients [
44].
Nutritional therapy and education
Malnutrition is highly prevalent in patients with liver cirrhosis [
45] and may contribute to the development of complications such as ascites and hepatorenal syndrome [
46]. In particular, sarcopenia, which is commonly observed in cirrhotic patients, is closely associated with increased mortality [
47], and pretransplant malnutrition or sarcopenia has been reported as a risk factor for postoperative complications and mortality in liver transplant recipients [
48–
50]. Therefore, proactive nutritional assessment and therapeutic intervention are essential in patients with cirrhosis. In general, energy intake of 30–35 kcal/kg/day is recommended for patients with cirrhosis [
51]. Higher caloric intake may be required in the presence of acute complications or refractory ascites, which are associated with increased energy expenditure [
51]. Daily protein intake of 1.2–1.5 g/kg is recommended, and higher intake of approximately 1.5 g/kg/day should be considered in patients with malnutrition or sarcopenia [
51]. Prolonged fasting should be avoided, as it promotes protein catabolism and muscle wasting. A late evening snack (LES) shortens the nocturnal fasting period and helps maintain an anabolic state. Meta-analyses including randomized controlled trials have demonstrated that LES is associated with beneficial effects on multiple clinical outcomes, including prevention of sarcopenia, increases in serum albumin levels, and reductions in the incidence of ascites [
52,
53]. In particular, LES has been shown to be more favorable for protein metabolism than equivalent caloric intake during daytime [
54], and the use of oral nutritional supplements containing branched-chain amino acids (BCAAs) may be considered.
In cirrhotic patients with low serum albumin levels, long-term BCAA supplementation has been shown to improve nitrogen balance and ameliorate hepatic encephalopathy as well as liver function test abnormalities [
55,
56]. In a study of 204 patients with decompensated cirrhosis, 24 weeks of BCAA supplementation resulted in improved serum albumin levels and reduced development of ascites and peripheral edema [
57]. In a randomized controlled trial involving patients with Child–Pugh class A cirrhosis, BCAA supplementation for more than one year was associated with a significantly lower incidence of ascites [
58]. Another study in 21 patients with cirrhosis demonstrated improved serum albumin levels and increased muscle mass following BCAA supplementation [
59]. In addition, a high-protein diet (1.2 g/kg/day) combined with a high-fiber diet (30 g/day) and BCAA supplementation was associated with increased muscle mass and prevention of hepatic encephalopathy [
60]. In patients undergoing hepatic resection for hepatocellular carcinoma, BCAA supplementation was effective in preventing ascites and pleural effusion [
61]. Long-term BCAA administration has also been associated with improvements in serum bilirubin levels, Child–Pugh scores, serum albumin levels, and overall survival in patients with cirrhosis [
62,
63]. Furthermore, a recent large-scale multicenter propensity score–matched cohort study demonstrated that BCAA supplementation was associated with reduced risk of major complications, including hepatic encephalopathy, SBP, and falls, as well as decreased emergency department visits and hospitalization rates [
64]. These findings from individual studies have been consistently supported by recent meta-analyses. Konstantis et al. reported that BCAA supplementation significantly increased serum albumin levels and reduced the risk of major complications, including hepatic encephalopathy and worsening ascites, in patients with cirrhosis [
65]. Another meta-analysis demonstrated that BCAA supplementation for more than six months was significantly associated with improved event-free survival in patients with chronic liver disease [
66]. Based on these findings, BCAA supplementation may be considered to improve nutritional status and control complications in patients with cirrhosis, including those with ascites.
Long-term oral or enteral nutritional therapy may also be beneficial for improving nutritional status and reducing complications in patients with cirrhosis. Recent small randomized controlled trials demonstrated that intensive nutritional interventions in patients with decompensated cirrhosis lead to improvements in muscle strength and liver function scores, significantly reduce hospitalization rates, and improve survival [
67,
68]. In a randomized controlled trial involving liver transplant candidates with severe malnutrition, nocturnal enteral feeding via a nasogastric tube did not significantly reduce mortality or infection rates but was effective at improving muscle strength and nutritional status, suggesting that nutritional rehabilitation is feasible even in severely malnourished patients [
69]. At present, there are no definitive recommendations regarding routine vitamin or mineral supplementation in patients with cirrhotic ascites. However, in patients with documented nutritional deficiencies, supplementation with vitamin A, thiamine, vitamin B12, folate, pyridoxine, vitamin D, and zinc may be considered part of nutritional therapy [
51]. Zinc supplementation, which is involved in albumin and BCAA metabolism, has been reported to improve ascites and hepatic encephalopathy [
70,
71].
Observational studies have shown improved survival in patients with cirrhosis who received multidisciplinary care involving nutrition support teams and regular education [
72], and randomized controlled trials have demonstrated that nutritional therapy reduces the recurrence of hepatic encephalopathy and hospitalization [
73]. Meta-analyses have further shown that various nutritional interventions, including high-protein diets, LESs, and BCAA supplementation, contribute to improvements in muscle mass and nutritional parameters [
74]. These findings indicate that simple dietary advice alone is insufficient and underscore the need for more structured and individualized nutritional management. Therefore, comprehensive multidisciplinary nutritional counseling, including individualized nutritional therapy and education, is recommended for patients with cirrhosis, and recent evidence suggests the importance of integrated approaches combining nutritional and psychosocial support [
75].
Dietary sodium restriction
Ascites in patients with liver cirrhosis is associated with impaired renal sodium handling, and is therefore managed through dietary sodium restriction and diuretic therapy [
76]. A low-sodium diet facilitates better control of ascites and may shorten hospital stay. The recommended daily sodium intake is less than 5 g of salt (2,000 mg of sodium, or 88 mmol per day). Because strict sodium restriction may result in reduced food intake and nutritional deficiencies [
51,
77], a moderate sodium intake may be permitted with appropriate adjustment of diuretic therapy in patients who have difficulty adhering to sodium restriction. Since water is passively excreted through renal sodium excretion, fluid restriction is not routinely required in most patients with ascites.
Diuretics
In patients with moderate to severe cirrhotic ascites, dietary sodium restriction alone is rarely sufficient for symptom control. Therefore, diuretics are initiated to promote faster resolution of ascites and to restore sodium balance [
78]. Diuretics should be administered orally, as intravenous use is not recommended due to the risk of AKI from rapid fluid shifts.
Secondary hyperaldosteronism is commonly observed in cirrhotic patients with ascites. It promotes sodium and water reabsorption in the distal tubules and collecting ducts, leading to hypokalemia. As aldosterone antagonists directly block this pathophysiology, they are considered first-line agents in diuretic therapy for cirrhotic ascites. Spironolactone has a long half-life and slow onset of action, requiring 3–4 days to reach a steady-state concentration. The recommended starting dose is 50–100 mg/day, which can be titrated every 3–5 days as needed. The maximum daily dose is 400 mg. Potential adverse effects include hyperkalemia, gynecomastia, mastalgia, reduced libido, and erectile dysfunction [
79]. Although amiloride is less potent than spironolactone as a diuretic, it has a lower risk of antiandrogenic side effects. It can be a useful alternative in patients who develop gynecomastia or breast tenderness during spironolactone therapy and is typically administered at one-tenth the dose of spironolactone [
80].
Loop diuretics exert their effect by inhibiting the Na
+-K
+-2Cl
− cotransporter in the thick ascending limb of the loop of Henle. Furosemide, the most commonly used loop diuretic, has a more rapid onset of action than spironolactone. While it may cause hypokalemia, it also has the advantage of correcting hyperkalemia associated with aldosterone antagonists. The usual starting dose is 20–40 mg per day, with titration up to 160 mg as needed. Torasemide has a longer comparative half-life and duration of action compared with furosemide and is used at approximately half the dose of furosemide [
81].
Aldosterone antagonists are the first-line diuretics for the treatment of ascites in liver cirrhosis. Loop diuretics may be added sequentially or started concurrently, depending on the clinical situation [
82]. Monotherapy with loop diuretics is not recommended, as it is less effective than aldosterone antagonist monotherapy. When there is an inadequate response to spironolactone or hyperkalemia occurs, furosemide should be added [
82]. Combination therapy typically involves initiating both agents simultaneously at a ratio that maintains serum potassium balance, commonly 100 mg of spironolactone with 40 mg of furosemide. In patients with recurrent ascites, this combination has led to faster resolution of ascites and lower risk of hyperkalemia compared to spironolactone alone [
83].
During the early phase of diuretic therapy, it is essential to regularly monitor the patient’s body weight, vital signs, mental status, serum creatinine, serum sodium, and potassium levels, and spot urine sodium and potassium concentrations to assess both efficacy and potential adverse effects. Tracking the degree of weight loss during salt restriction and diuretic therapy is crucial to evaluate treatment response and prevent complications. In patients without peripheral edema, weight loss exceeding 0.5 kg per day may indicate intravascular volume depletion and may lead to renal impairment or hyponatremia, and should therefore be avoided [
6,
84]. For patients with peripheral edema, weight loss of up to 1 kg per day is generally considered acceptable [
6,
85]. Measuring 24-hour urinary sodium excretion can help evaluate the effectiveness of dietary sodium restriction and the adequacy of the diuretic dose [
4,
6]. Daily salt intake of 5 g corresponds to 88 mmol of sodium, and considering an average loss of 10 mmol per day through non-urinary routes such as sweat, target urinary sodium excretion should be approximately 78 mmol per day. Insufficient weight loss despite sodium restriction and 24-hour urinary sodium below 78 mmol may indicate inadequate diuretic response, warranting dose escalation. Since 24-hour urine collection is cumbersome, the spot urine sodium-to-potassium ratio can be used as an alternative [
86]. If the spot urine sodium/potassium ratio exceeds 1 but sufficient weight loss is not observed, inadequate dietary sodium restriction should be suspected. Conversely, a ratio below 1 suggests inadequate natriuresis, and an increase in the diuretic dose may be considered. This test can be performed at any time of day, as there is no significant diurnal variation in the values [
87].
Once ascites is controlled, diuretics should be maintained at the lowest effective dose to minimize adverse events. These complications occur in approximately 19–40% of patients and commonly include electrolyte imbalances, renal dysfunction, and hepatic encephalopathy [
88]. If serum sodium levels fall below 125 mmol/L, cautious dose reduction or discontinuation of diuretics should be considered, and fluid restriction may be initiated [
77]. If hypokalemia occurs, loop diuretics should be reduced or discontinued. Conversely, if serum potassium levels increase above the normal upper limit, aldosterone antagonist dosage should be adjusted accordingly.
Muscle cramps are commonly observed in patients with liver cirrhosis and may significantly impair quality of life [
89]. Diuretic use for ascites control has been associated with increased frequency and severity of cramps [
90]. Albumin infusion (20–40 g per week) has shown beneficial effects in reducing both the frequency and intensity of cramps [
91]. In a randomized controlled trial, baclofen (initiated at 10 mg/day and titrated weekly up to 30 mg/day) significantly reduced cramp frequency and improved sleep quality without notable adverse effects [
92]. Orphenadrine [
93] and methocarbamol [
94] have also demonstrated potential symptom relief in some studies. Recently, a randomized controlled trial evaluating pregabalin (75–150 mg/day) reported trends toward reduced cramp frequency and improved quality of life, although early termination due to insufficient enrollment warrants cautious interpretation of the results [
95]. The most commonly reported adverse events were dizziness and drowsiness, which were generally mild. Given the overall mild nature of reported adverse events, pharmacologic therapy may be considered in cirrhotic patients whose quality of life is significantly affected by muscle cramps.
Albumin
Albumin facilitates the renal transport of loop diuretics [
96]. Its administration has been shown to enhance diuretic response and reduce the length of hospital stay [
97]. Meta-analyses have demonstrated that albumin infusion significantly decreases the incidence of complications associated with LVP and reduces mortality [
98]. In a randomized controlled trial involving patients with SBP, albumin administration reduced the incidence of hepatorenal syndrome [
99]. In another study, patients receiving albumin showed significantly improved circulatory function, characterized by increased arterial pressure and suppressed plasma renin activity, compared to those receiving hydroxyethyl starch [
100]. According to an Italian study, administration of 6 to 8 g of albumin per liter of ascitic fluid removed is recommended when more than 5L is removed during LVP [
101]. For SBP patients at high risk of renal impairment (total bilirubin > 4 mg/dL or serum creatinine > 1 mg/dL), the recommended dose is 1.5 g/kg on the day of diagnosis and 1 g/kg on day 3 [
101].
The ANSWER trial, a randomized controlled study investigating the long-term effects of albumin therapy in patients with cirrhosis and ascites, demonstrated that weekly albumin infusion (40 g/week) significantly reduced the need for therapeutic paracentesis, the incidence of cirrhosis-related complications, and improved 18-month survival (77% vs. 66%,
P=0.028) compared to standard care [
102]. In contrast, the MACHT trial, which evaluated albumin infusion (40 g every 15 days) in 196 cirrhotic patients with ascites awaiting liver transplantation, found no significant differences in complication rates or one-year mortality [
103]. The discrepancy between the two studies may be explained by differences in albumin dosing and treatment duration: the cumulative albumin dose in the MACHT trial was approximately half that of the ANSWER trial, and the median treatment duration was considerably shorter (63 days vs. over 1 year).
The current guideline committee conducted a systematic review and meta-analysis to evaluate the efficacy of albumin in patients undergoing LVP, including a total of 26 studies (
Supplementary Material 3). While albumin administration did not significantly reduce overall mortality, it was associated with decreased risk of paracentesis-induced circulatory dysfunction (PICD; RR 0.45, 95% CI 0.34–0.59). In subgroup analyses, a significant reduction in the risk of AKI was observed only when more than 6 g of albumin per L of ascites was administered (RR 0.55, 95% CI 0.36–0.85). The risk of hyponatremia was also significantly reduced when albumin was given at ≥6 g/L (RR 0.45, 95% CI 0.27–0.74) and when the total volume removed was less than 9 L (RR 0.49, 95% CI 0.32–0.75).
Therefore, albumin administration may help reduce the risk of AKI in patients with cirrhotic ascites. However, the included studies varied widely in albumin dosage, frequency, and duration, limiting the generalizability of effect estimates. Further large-scale randomized controlled trials using standardized albumin regimens are warranted.
Large-volume paracentesis
For patients with grade 3 tense ascites, LVP is recommended as the initial treatment. LVP is defined as the removal of more than 5 L of ascitic fluid in a single procedure, which can rapidly relieve abdominal distension. In patients with significant peripheral edema, redistribution of interstitial fluid into the peritoneal cavity may occur after the first LVP, necessitating repeat paracentesis within a short period [
85,
104]. Therefore, sodium restriction and the use of diuretics are important to prevent recurrence of ascites.
LVP can lead to PICD, which is associated with serious complications including AKI, hepatorenal syndrome, dilutional hyponatremia, hepatic encephalopathy, and death [
105,
106]. To prevent PICD, albumin infusion is recommended during LVP. Administration of 6–8 g of albumin per liter of ascites removed has been shown to reduce the risk of PICD [
85,
107]. Although no strict upper limit for the volume of ascites removed in a single session has been firmly established, a study in patients with refractory ascites found that limiting the volume to less than 8 L and administering a mean of 9 g (minimum 6 g) of albumin per liter of fluid removed did not increase the long-term risk of renal dysfunction or cirrhosis-related complications, even in cases where PICD occurred [
108]. This study suggests that limiting the volume to less than 8 L may help minimize the risk of PICD-related complications. However, these findings may not be generalizable to patients with impaired baseline renal function or those requiring more than 8 L of fluid removal, and further large-scale studies are needed to establish a clear upper limit.
The current guideline committee conducted a systematic review and meta-analysis to evaluate the efficacy of albumin in patients undergoing LVP, including a total of 26 studies (
Supplementary Material 3). While albumin administration did not significantly reduce overall mortality, it was associated with decreased risk of PICD (odds ratio [OR] 0.32, 95% CI 0.22–0.47). In subgroup analyses, a significant reduction in the risk of AKI was observed only when more than 6 g of albumin per L of ascites was administered (OR 0.47, 95% CI 0.23–0.96). The risk of hyponatremia was also significantly reduced when albumin was given at ≥6 g/L (OR 0.31, 95% CI 0.13–0.71) and when the total volume removed was less than 9 L (OR 0.36, 95% CI 0.18–0.73).
Therefore, albumin infusion during LVP is beneficial in reducing the risk of PICD, AKI, and hyponatremia. Clinically, it is recommended to administer 6–8 g of albumin per liter of ascites removed and to avoid excessive fluid removal in a single session.
Areas requiring further research
Nutritional therapy in patients with cirrhosis and ascites has been shown in multiple studies to reduce major complications of cirrhosis. However, a multidisciplinary, structured model for nutritional intervention is lacking, and further research is warranted to establish such an approach. Although the clinical benefits of albumin therapy in patients with cirrhotic ascites have been demonstrated, there remain unresolved issues, including the absence of standardized treatment strategies regarding dose and duration, and the lack of risk-based, individualized treatment algorithms. Large-scale randomized controlled trials are needed to identify more precise patient subgroups and to evaluate the long-term therapeutic efficacy of albumin administration.
Recommendations
1. Treatment of underlying liver disease is important for controlling ascites in patients with liver cirrhosis. (A1)
2. For patients with cirrhotic ascites, energy intake of 30–35 kcal/kg/day and protein intake of 1.2–1.5 g/kg/day is recommended. (B1) Late evening snacks and branched-chain amino acid supplementation are recommended to support the management of ascites and related complications in patients with cirrhosis. (B1)
3. A sodium-restricted diet (salt <5 g/day, equivalent to sodium <2,000 mg or 88 mmol/day) is recommended for patients with cirrhotic ascites. (B1) Fluid restriction is not required unless the patient presents with severe hyponatremia (serum sodium <125 mmol/L). (B1)
4. Spironolactone, an aldosterone antagonist, is recommended as the first-line diuretic for patients with cirrhotic ascites, with furosemide added as needed to enhance the diuretic response. (A1) During diuretic therapy, careful monitoring for complications such as acute kidney injury and electrolyte disturbances is necessary. (A1)
5. For patients with tense ascites, large-volume paracentesis (LVP) is the first-line treatment. (A1) During LVP, intravenous albumin infusion at a dose of 6–8 g per liter of ascitic fluid removed is recommended. (A1)
REFRACTORY ASCITES
Definition and diagnostic criteria
Refractory ascites is defined as ascites that cannot be mobilized or that recurs early despite dietary sodium restriction and maximal tolerated doses of diuretics (spironolactone up to 400 mg/day and furosemide up to 160 mg/day). It also encompasses cases where effective diuretic therapy cannot be maintained due to diuretic-related complications [
109–
111]. Consequently, refractory ascites is further classified into diuretic-resistant ascites and diuretic-intractable ascites (
Table 5) [
85,
112].
Large-volume paracentesis
Patients with refractory ascites should maintain a low-sodium diet and undergo repeated LVP to control ascites. LVP is an effective treatment for refractory ascites but should not be applied as a first-line therapy in all patients. It is selectively performed in patients with severe abdominal distension causing discomfort, impaired oral intake, or respiratory compromise. Compared with diuretic therapy, LVP combined with albumin infusion shortens hospital stay and reduces the incidence of hyponatremia, renal dysfunction, and hepatic encephalopathy; however, repeated procedures may increase the risk of infection and protein depletion, leading to malnutrition [
113]. PICD may occur after LVP and requires careful prevention. To reduce this risk, intravenous albumin infusion (6–8 g per liter of ascites removed) is strongly recommended.
The volume and frequency of paracentesis should be individualized based on dietary sodium intake. In Korea, average daily sodium intake is approximately 4,500–7,000 mg. Through strict dietary salt restriction (<5 g/day), daily sodium intake can be effectively reduced to ≤2,000 mg [
114]. However, considering that patients with refractory ascites typically excrete ≤450 mg/day of sodium in urine, and lose approximately 200 mg via non-urinary routes, a net positive sodium balance of approximately 1,350 mg/day persists even after successful dietary modifications. This inevitable fluid retention necessitates repeated LVP.
Pharmacologic therapy
Evidence supporting the utility of continued diuretic therapy in refractory ascites remains limited. In patients with diuretic-resistant refractory ascites, escalating diuretics to maximal doses typically fails to increase natriuresis or mobilize fluid while significantly increasing the risk of renal dysfunction and electrolyte imbalance [
6]. Similarly, in patients with diuretic-intractable refractory ascites, the safety of reintroducing diuretics at doses lower than those that previously caused adverse events remains uncertain.
Adjunctive therapy with midodrine (oral α
1-adrenergic agonist, 7.5 mg every 8 hours) has been reported to improve systemic hemodynamics and ascites control [
115]. Small-scale studies have shown that midodrine increases urine volume, urinary sodium excretion, and mean arterial pressure, potentially improving survival [
116]. Consequently, it may be considered in pharmacologic management of refractory ascites. However, as most data are derived from small exploratory trials, further large-scale studies are required to confirm its long-term efficacy and safety.
Clonidine (an α
2-adrenoceptor agonist, 0.1 mg every 12 hours) combined with diuretics has also shown potential for improving diuretic responsiveness and reducing readmissions for LVP. However, significant interindividual variability in response, attributed to α
2-adrenoceptor polymorphisms, has been observed [
117].
While non-selective beta-blockers (NSBB) are the standard of care for preventing variceal bleeding, their safety in refractory ascites remains controversial. Early studies suggested that NSBBs might precipitate PICD, worsen renal function, and lower mean arterial pressure [
118,
119]. Conversely, recent evidence indicated that NSBB use is not consistently associated with increased AKI or mortality [
120–
125], and some studies reported improved survival [
126]. The choice of NSBB agent and dosage appears to be clinically relevant. Propranolol at doses ≤80 mg/day has been associated with improved outcomes [
127]. In contrast, carvedilol, which has additional α
1-blocking effects, was associated with increased mortality [
122,
128]. Therefore, if NSBBs are indicated, careful monitoring of blood pressure and renal function is required, and dose reduction or discontinuation should be considered in cases of hypotension or renal impairment.
A meta-analysis of nine studies reported that low-dose tolvaptan (oral vasopressin V2-receptor antagonist, approximately 7.5 mg/day) improved survival (hazard ratio [HR], 0.42), reduced body weight (HR, 0.44), and ameliorated hyponatremia (HR, 0.35) in patients with refractory ascites [
129]. However, as most studies were conducted in Japan, the generalizability of these findings to other populations requires further validation. Recent small-scale studies suggested that empagliflozin, a sodium-glucose cotransporter 2 inhibitor, may improve ascites control [
130,
131]. While empagliflozin has been shown to reduce the need for LVP and the incidence of AKI, its use is associated with increased frequency of hyponatremia and muscle cramps [
130].
Albumin
In a multicenter randomized controlled trial involving patients with cirrhosis and ascites, long-term albumin administration (40 g weekly) significantly improved 18-month survival compared with standard care alone (77% vs. 66%,
P=0.028). This survival benefit was attributed to better management of fluid accumulation and a reduction in cirrhosis-related complications [
102]. Similarly, a prospective non-randomized study of 70 patients with refractory ascites demonstrated that administering 20 g of albumin twice weekly reduced 24-month mortality and hospital readmission rates, while also lowering the risk of hepatic encephalopathy and hepatorenal syndrome [
132]. In another study involving 312 patients with ascites (83 patients with refractory ascites), albumin therapy (40 g every two weeks) for 10 months resulted in the resolution or improvement of ascites in 26% of patients with refractory subgroup, with no significant albumin-related adverse events [
133]. Collectively, these findings suggest that long-term albumin therapy is relatively safe and may offer clinical benefits in refractory ascites. However, given the heterogeneity in patient selection, dosing regimens, and treatment duration across studies, cautious interpretation and patient-specific decision-making are warranted.
Transjugular intrahepatic portosystemic shunt
A meta-analysis of seven randomized controlled trials demonstrated that TIPS significantly improves ascites control compared with repeated LVP plus albumin (
Supplementary Material 4). Complete resolution of ascites without the need for paracentesis was achieved in 56% of patients in the TIPS group compared with only 16% in the control group (OR 7.67, 95% CI 4.73–12.45). In the same meta-analysis, TIPS was associated with improved survival compared with control therapy (HR 0.59, 95% CI 0.45–0.76). However, clinicians should note that the resolution of ascites following TIPS is often gradual. Therefore, most patients require continued dietary salt restriction and diuretic therapy in the immediate post-procedural period. As TIPS effectively lowers portal pressure and restores diuretic sensitivity, diuretic dosages must be carefully monitored and adjusted to prevent dehydration and renal impairment.
Regarding complications, there was no significant difference between TIPS and LVP groups in the risk of hepatorenal syndrome or SBP. However, the risk of hepatic encephalopathy was significantly higher in the TIPS group (OR 1.80, 95% CI 1.15–2.80), particularly when uncovered stents were used. In contrast, the use of polytetrafluoroethylene-covered stents has been shown to mitigate this risk, with no significant increase in hepatic encephalopathy compared to control groups in subgroup analysis. Nevertheless, when data from retrospective cohort studies were pooled [
134,
135], the increased risk of hepatic encephalopathy remained significant.
Because TIPS is associated with significant complications, it should not be applied indiscriminately. Careful patient selection is critical to maximize survival benefit and minimize adverse events. Better outcomes have been reported in patients without prior hepatic encephalopathy, with Child–Pugh class B, lower MELD scores, and preserved cardiac function [
136–
138]. Advanced age, recurrent hepatic encephalopathy, hyperbilirubinemia, and Child–Pugh class C cirrhosis are associated with increased post-procedural complications and liver failure [
139]. The concept of “preemptive TIPS” in patients with large-volume ascites prior to the development of refractory ascites has been proposed, and randomized trials are ongoing [
140,
141]; currently, however, evidence is insufficient to recommend routine preemptive TIPS for patients who do not meet the criteria for refractory ascites.
Liver transplantation
Refractory ascites is associated with a dismal prognosis, characterized by a 6-month mortality rate of approximately 21% and median survival of less than 1 year [
142,
143]. Consequently, prompt evaluation for liver transplantation is mandated for all eligible candidates. Clinicians should be aware that the severity of liver disease with refractory ascites is often underestimated by the original MELD score, particularly in those with scores <21. Furthermore, hyponatremia, a frequent complication in this population, is an independent predictor of mortality. To address these limitations, the MELD-Na and MELD 3.0 scoring systems, which incorporate serum sodium levels, have been developed to provide more accurate risk stratification [
144,
145].
Other experimental approaches
Peritoneovenous shunting has been utilized since the 1970s for refractory ascites; however, it is associated with high complication rates and no survival advantage over standard medical therapy [
146]. Currently, it may be considered a salvage therapy in selected patients who are ineligible for liver transplantation or TIPS, and for whom repeated LVP is not feasible due to limited access or abdominal scarring.
The alfapump
® system is an implantable device that transfers ascitic fluid from the peritoneal cavity to the urinary bladder [
147]. The device is implanted subcutaneously and drains ascites via a catheter. Contraindications include loculated ascites, active infection, or extensive intra-abdominal adhesions. Furthermore, surgical morbidity and mortality must be carefully weighed in patients with advanced cirrhosis. While multicenter observational studies and one randomized trial reported significant improvement in ascites control [
147–
149], concerns regarding the deterioration of renal function remain [
148,
149].
For patients with refractory ascites who are ineligible for liver transplantation or TIPS, long-term abdominal drains (LTADs) may be considered as a management strategy. A systematic review indicated that LTAD use eliminated the need for additional LVP without adversely affecting overall mortality; however, daily drainage exceeding 1.5 L was associated with increased risk of renal dysfunction [
150]. Regarding tunneled intraperitoneal catheters, a retrospective study of 223 TIPS-contraindicated patients reported a mortality reduction compared to standard care. Yet, this benefit was accompanied by higher risk of AKI and rehospitalization, underscoring the need for careful patient selection [
151]. Conversely, a single-center study of 44 patients using tunneled pigtail catheters demonstrated favorable outcomes, including reduced hospital admission and shorter length of stay [
152]. Recent studies have also evaluated non-tunneled catheters for short-term drainage. In a retrospective study of 192 patients with grade 3 ascites, 7-F, 8-cm catheters placed under ultrasound guidance (median duration: 48 hours) effectively reduced repeated LVPs but were associated with complications such as AKI (15.1%), infection (4.3%), and bleeding (0.3%) [
153]. Similarly, another study highlighted safety concerns, reporting an approximately 10% incidence of bacterial peritonitis following placement [
154]. Despite the widespread use of non-tunneled catheters in clinical practice in Korea, data regarding their long-term safety and complications remain insufficient, necessitating further investigation.
Cell-free and concentrated ascites reinfusion therapy may be considered during LVP, particularly in patients with a small body habitus. This technique involves filtering cells from drained ascitic fluid and concentrating the protein-rich fraction for reinfusion, potentially reducing the need for exogenous albumin. Several studies have reported efficacy comparable to albumin infusion with reduced albumin requirements [
155–
157]; however, large-scale randomized controlled trials confirming these findings are currently lacking.
Areas requiring further research
Current definitions of refractory ascites encompass both diuretic-resistant and diuretic-intractable ascites, with strict dietary salt restriction serving as a key prerequisite. Within this framework, classifying those with poor adherence to a low-salt diet is challenging. Many studies define refractory ascites based solely on the frequency of paracentesis, without verifying strict adherence to a low-sodium diet (sodium intake <2,000 mg/day). Thus, patients who fail to maintain strict dietary sodium restriction could have been included in refractory ascites. Further studies are needed to clarify the impact of dietary adherence on definition accuracy and clinical outcomes of refractory ascites.
Effective treatment options for diuretic-intractable ascites remain limited. A significant proportion of these patients are at high risk for complications from TIPS, often leaving repeated LVP as the sole management option. Future research should prioritize this subgroup, focusing on optimizing diuretic strategies, and developing novel non-pharmacologic therapies with proven efficacy and safety profiles.
Recommendations
1. Patients with refractory ascites should be managed with dietary salt restriction and repeated large-volume paracentesis with albumin infusion. Liver transplantation should be considered in eligible candidates. (A1)
2. Transjugular intrahepatic portosystemic shunt may be considered in carefully selected patients with refractory ascites. (A2)
HYPONATREMIA
Definition, classification, and clinical manifestations
Hyponatremia is one of the most common complications observed in patients with advanced liver cirrhosis, and is generally defined as a serum sodium concentration ≤135 mmol/L. In patients with liver cirrhosis, serum sodium levels between 130–135 mmol/L are classified as mild hyponatremia, with a prevalence of approximately 30–55% [
158–
161]. Levels of 125–129 mmol/L are considered moderate hyponatremia, and levels <125 mmol/L are defined as severe hyponatremia, with a combined prevalence of moderate-to-severe hyponatremia of approximately 15–30% [
158,
159,
162,
163]. The prevalence of hyponatremia increases with worsening liver function, occurring in 15–20% of patients with Child–Pugh class A cirrhosis and 30–40% of those with Child–Pugh class B or C [
158,
161].
In cirrhosis, hyponatremia is commonly dilutional hyper-volemic hyponatremia. However, pseudohyponatremia, hypovolemic hyponatremia, and euvolemic hyponatremia should be distinguished. Serum osmolality is helpful for this differentiation. Causes of pseudohyponatremia include hypertriglyceridemia, hyperproteinemia, and mannitol administration [
164]. In patients with hypovolemic hyponatremia due to diuretic overuse or dehydration, diuretics should be withheld and volume replacement should be prioritized. In patients with euvolemic hyponatremia, potential underlying causes such as hypothyroidism, adrenal insufficiency, and the syndrome of inappropriate antidiuretic hormone secretion should be systematically evaluated. Management may include fluid restriction and, in select cases, pharmacologic therapy [
165].
Most patients with mild hyponatremia (130–135 mmol/L) are asymptomatic; therefore, clinical concern generally increases when serum sodium falls to ≤130 mmol/L [
166]. In one study, ascites and a serum sodium level ≤130 mmol/L were associated with significantly increased risk of SBP (OR 3.40), hepatorenal syndrome (OR 3.45), and hepatic encephalopathy (OR 2.36) [
158]. Persistent hyponatremia is associated with cognitive dysfunction and impaired quality of life [
167], and it adversely affects post-transplant outcomes [
162,
168]. Management should consider clinical symptoms, associated complications, and residual liver function.
Symptoms of hyponatremia include nausea, anorexia, cognitive impairment, headache, gait disturbance, and falls [
165]. Moderate hyponatremia (125–130 mmol/L) is often asymptomatic or nonspecific, whereas more severe reductions are associated with overt symptoms and poor prognosis [
169]. In clinical practice, it may be difficult to distinguish symptoms caused by hyponatremia from those due to hepatic encephalopathy or other etiologies.
Hypervolemic hyponatremia in cirrhosis is primarily driven by progressive portal hypertension, leading to systemic vasodilatation, reduced effective arterial blood volume, and secondary water retention [
170]. As cirrhosis advances, reduced systemic vascular resistance, decreased mean arterial pressure, and increased cardiac output result in a hyperdynamic circulation [
164,
171]. Accumulation of vasodilatory substances including nitric oxide, glucagon, vasoactive intestinal peptide, substance P, platelet-activating factor, prostaglandins, and prostacyclins plays a key role in splanchnic arterial vasodilatation [
172].
Systemic vasodilatation and reduced effective arterial volume activate the renin–angiotensin–aldosterone system, promoting sodium and water retention, which manifests clinically as peripheral edema and ascites [
173]. In decompensated cirrhosis, impaired regulation of antidiuretic hormone (ADH) further exacerbates hyponatremia [
174]. Increased atrial natriuretic peptide levels, reduced prostaglandin E
2, and impaired ADH degradation also contribute to worsening hyponatremia [
173].
Management of hypervolemic hyponatremia due to advanced cirrhosis is challenging. Evidence supporting routine discontinuation of diuretics is limited, and withdrawal may worsen ascites and increase the need for repeated paracentesis. Nevertheless, several therapeutic approaches may be considered.
Fluid restriction and intravenous fluids
The most commonly adopted initial strategy is restriction of sodium and fluid intake. A low-sodium diet (<2,000 mg/day) is generally recommended [
6]. In severe hyponatremia (120–125 mmol/L), fluid intake may be restricted to 1–1.5 L/day, and in selected cases to as little as 500 mL/day after accounting for insensible water loss [
175,
176]. However, adherence is often poor, and clinical evidence supporting this approach remains limited [
165].
Few studies have specifically evaluated strict fluid restriction in cirrhosis. In trials where fluid restriction was combined with diuretics or albumin, intake was typically limited to approximately 1 L/day [
167,
177]. In one study, only 36% of patients achieved an increase in serum sodium ≥5 mmol/L after 3 days of fluid restriction [
178], indicating that fluid restriction alone is often insufficient and should be combined with other therapies [
179].
Hypertonic saline is generally not recommended because it may worsen ascites, edema, and pulmonary congestion. Rapid correction of hyponatremia increases the risk of osmotic demyelination syndrome (ODS); therefore, hypertonic saline should be reserved for life-threatening situations such as seizures, profound neurologic symptoms, or serum sodium <110 mmol/L [
176].
ODS is characterized by altered consciousness, dysarthria, and dysphagia, with characteristic magnetic resonance imaging findings involving the pons, basal ganglia, thalamus, and cerebellum [
180]. Although rare, it occurs in approximately 0.02% of cirrhotic patients [
181] and is associated with severe hyponatremia (<110 mmol/L), alcohol use, hypokalemia [
182], hypophosphatemia, hypoglycemia, prior hepatic encephalopathy, and male sex. The diagnosis should be established using brain magnetic resonance imaging [
175,
183,
184].
Albumin
Several studies suggest that albumin administration may improve hyponatremia. Although the precise mechanism remains unclear, albumin is thought to expand plasma volume, increase urinary free-water clearance, and promote water excretion [
164]. In a retrospective study of 1,126 cirrhotic patients with serum sodium <130 mmol/L, those who received albumin (mean cumulative dose 225 g) showed greater improvement in hyponatremia compared with those who did not (69% vs. 61%,
P=0.009), with a larger mean increase in serum sodium (8.47 vs. 5.81 mmol/L,
P<0.01) [
185]. Albumin administration was also associated with improved short-term survival in patients with AKI, SBP, or those undergoing LVP, regardless of indication [
185]. In the ANSWER trial, long-term, regular albumin administration for 18 months in patients with cirrhosis and ascites improved hyponatremia (<130 mmol/L) by 49% compared with standard medical therapy alone (
P<0.01). In this study, patients received 40 g of 20% human albumin twice weekly during the first two weeks, followed by 40 g weekly thereafter. Albumin treatment was associated with a 49% reduction in the incidence of hyponatremia (serum sodium <130 mmol/L;
P<0.01). Furthermore, long-term albumin administration was shown to improve overall survival and quality of life, and to reduce the need for hospitalization, LVP, refractory ascites, SBP, and hepatic encephalopathy [
102]. Collectively, these findings support a beneficial role of albumin therapy in improving hyponatremia in patients with cirrhosis.
Tolvaptan
Vasopressin receptor antagonists have been widely used in the management of hypervolemic hyponatremia and euvolemic hyponatremia. These agents selectively antagonize the vasopressin V2 receptor located on the principal cells of the renal collecting duct. By inhibiting arginine vasopressin–mediated free water reabsorption, which is pathophysiologically increased in response to systemic vasodilation and a reduction in effective arterial blood volume, these drugs enhance electrolyte-free water excretion and thereby correct dilutional hyponatremia. Tolvaptan is currently the only orally available selective V2 receptor antagonist. In a phase III trial in which tolvaptan was administered at doses of 15–60 mg daily for 30 days, a subgroup analysis of 120 patients with liver cirrhosis demonstrated a significant improvement in serum sodium levels as early as day 4 of treatment in the tolvaptan group compared with placebo. This improvement was sustained throughout the treatment period up to day 30 and gradually declined toward baseline levels after discontinuation of therapy. Patients most commonly reported adverse events such as dry mouth and thirst; however, no serious treatment-related adverse events were observed in this study [
186].
In contrast, the SALTWATER study, which included 111 patients with hyponatremia, reported adverse events such as thirst, polyuria, and fatigue in approximately 3–10% of patients, as well as more serious complications including ODS, AKI, and gastrointestinal bleeding [
187]. Notably, this study employed relatively high doses of tolvaptan (60–120 mg), primarily in patients with autosomal dominant polycystic kidney disease. Due to these safety concerns, the U.S. Food and Drug Administration restricted the duration of tolvaptan use to a maximum of 30 days and issued recommendations against its use in patients with liver cirrhosis.
Nevertheless, subsequent studies from Japan, China, and other regions have evaluated low-dose tolvaptan (typically 3.75–7.5 mg daily) in patients with cirrhosis and have reported favorable outcomes, including improvement of hyponatremia, better ascites control, and increased urine output. Several observational studies and meta-analyses have consistently suggested potential benefits of low-dose tolvaptan with an acceptable safety profile in this population [
188–
190]. Therefore, further well-designed prospective studies are warranted to clarify the efficacy and safety of low-dose tolvaptan in patients with liver cirrhosis and dilutional hyponatremia.
Areas requiring further research
In patients with liver cirrhosis, the use of diuretics is essential for ascites control and prevention of related complications. However, diuretic therapy often needs to be discontinued due to the worsening of hyponatremia. Meanwhile, the clinical evidence supporting the efficacy of albumin for the management of hyponatremia remains insufficient, and clear guidance regarding the optimal initiation, continuation, or discontinuation of diuretics in the context of hyponatremia is lacking.
Therefore, it is necessary to elucidate the impact of combination therapy with albumin and diuretics on the correction of hyponatremia and on clinical outcomes, and to establish evidence-based therapeutic strategies for the management of cirrhotic patients with ascites and hyponatremia.
Recommendations
1. In patients with dilutional hyponatremia and serum sodium <120–125 mmol/L, fluid restriction to 1–1.5 L/day may be considered. (B1)
2. In cirrhotic patients with ascites and serum sodium <130 mmol/L, careful evaluation and management are required because of poor prognosis and increased risk of complications. (A1)
3. Albumin administration may be considered to facilitate correction of hyponatremia in patients with liver cirrhosis. (B1)
SPONTANEOUS BACTERIAL PERITONITIS
Definition and diagnostic criteria
Definition
SBP is defined as a primary infection of ascitic fluid caused by spontaneous bacterial invasion of the peritoneal cavity in the absence of any surgically treatable intra-abdominal source of infection. SBP develops in approximately 20–30% of patients with cirrhosis and ascites [
5]. It has been reported in 1.5–3.5% of outpatients and approximately 11.7% of hospitalized patients [
28,
191]. With early diagnosis and appropriate treatment, mortality has decreased to approximately 20% [
192]. According to the site of acquisition, SBP is classified as community-acquired SBP, hospital-acquired SBP (diagnosed 48–72 hours after hospitalization), and healthcare-associated SBP, which is diagnosed within 48 hours of hospital admission in patients with healthcare exposure within the preceding 90 days [
6].
Need for early diagnostic paracentesis when SBP is suspected
In patients with cirrhosis and ascites, SBP should be suspected and diagnostic paracentesis should be performed when symptoms or signs of peritonitis (abdominal pain, vomiting, ileus, abdominal tenderness), systemic inflammatory response (fever or hypothermia, chills, leukocytosis or leukopenia, tachycardia, tachypnea), or complications such as deterioration of liver function, hepatic encephalopathy, shock, renal failure, or gastrointestinal bleeding are present [
193]. However, SBP may be asymptomatic or present without typical features, manifesting only as complications, and therefore requires careful clinical attention [
191]. In an observational study including 239 patients with SBP, a delay of more than 12 hours in diagnostic paracentesis after hospital admission was associated with a 2.7-fold increase in mortality [
194]. Because SBP presents with diverse clinical manifestations and delayed treatment is associated with increased mortality, diagnostic paracentesis should be performed as early as possible when SBP is suspected.
Diagnosis
SBP is diagnosed when the polymorphonuclear leukocyte (PMN) count in ascitic fluid is ≥250/mm
3. When ascitic fluid is contaminated with red blood cells, the PMN count should be corrected by subtracting 1 PMN per 250 red blood cells/mm
3 [
193,
195]. Isolation of causative organisms from ascitic fluid or blood is important to guide antibiotic selection. Therefore, ascitic fluid culture should be obtained before initiating antibiotic therapy. Inoculation of at least 10 mL of ascitic fluid directly into blood culture bottles at bedside increases the diagnostic sensitivity to over 90% [
196]. Concomitant blood cultures further increase pathogen detection.
Approximately 40% of patients with ascitic PMN counts ≥250/mm
3 have negative ascitic cultures despite appropriate microbiological techniques; this condition is referred to as culture-negative neutrocytic ascites (CNNA). In a Korean retrospective study of 130 cirrhotic patients with peritonitis, the median survival of the CNNA group was 6.9 months, which was comparable to that of patients with culture-positive SBP (5.4 months) [
197]. Accordingly, CNNA should be treated in the same manner as culture-positive SBP.
Non-neutrocytic bacterascites is defined as ascitic fluid with a PMN count <250/mm
3 but positive bacterial culture. This condition may result from secondary bacterial colonization or spontaneous bacterial colonization of ascites. In a prospective study of 105 patients with culture-positive ascites, 31.9% had non-neutrocytic bacterascites, and 38% of these patients progressed to SBP within several hours [
198]. The in-hospital mortality rates were similar between nonneutrocytic bacterascites and SBP (31.8% vs. 45.7%). However, another study reported that asymptomatic nonneutrocytic bacterascites did not progress to SBP and had a lower 1-month mortality (27%) compared with SBP (62.1%) [
199]. Therefore, antibiotic therapy is indicated for nonneutrocytic bacterascites accompanied by symptoms or complications, whereas repeat paracentesis and close observation are appropriate in asymptomatic cases.
Secondary bacterial peritonitis
Approximately 5% of patients with cirrhosis develop peritonitis due to perforation or inflammation of intra-abdominal organs, referred to as secondary bacterial peritonitis [
200]. Secondary bacterial peritonitis is associated with a very high mortality rate of 50–80% and often requires surgical intervention; therefore, differentiation from SBP is crucial [
200]. Secondary bacterial peritonitis should be suspected in the presence of localized abdominal signs, polymicrobial growth in ascitic fluid culture, markedly elevated ascitic neutrophil counts, increased ascitic protein concentration (>1.0 g/dL), ascitic lactate dehydrogenase levels exceeding the upper limit of normal serum LDH, ascitic glucose ≤50 mg/dL, or the lack of a decrease in PMN count on repeat paracentesis performed 48 hours after appropriate antibiotic therapy [
32,
201]. Elevated ascitic carcinoembryonic antigen (>5 ng/mL) or alkaline phosphatase (>240 U/L) suggests bowel perforation [
202]. When secondary bacterial peritonitis is suspected, abdominal computed tomography should be performed immediately, and early surgical consultation is required.
Recommendations
1. When SBP is suspected, diagnostic paracentesis should be performed, and SBP is diagnosed when the ascitic PMN count is ≥250/mm3. (A1)
2. Ascitic fluid culture should be obtained before antibiotic administration to guide appropriate antimicrobial therapy. (B1)
Treatment of spontaneous bacterial peritonitis
When SBP is diagnosed, empirical antibiotic therapy should be initiated promptly before the results of ascitic fluid culture and antibiotic susceptibility testing become available. In a retrospective study of 635 patients with cirrhosis who developed septic shock, delays in appropriate antimicrobial therapy were associated with an increased risk of mortality (adjusted OR per hour delay 1.1, 95% CI 1.1–1.2) [
203].
Community-acquired spontaneous bacterial peritonitis
SBP is usually caused by a single pathogen; approximately 60% of cases are due to Gram-negative bacteria, whereas fungal infections account for less than 5%. SBP most commonly results from bacterial translocation from the intestine. In Korea, the most frequent causative organisms of SBP are
Escherichia coli, Klebsiella pneumoniae, and
Streptococcus species (
Table 6) [
204–
213]. Third-generation cephalosporins (ceftriaxone or cefotaxime) are recommended as empirical antibiotic therapy for community-acquired SBP.
Intravenous cefotaxime achieves high concentrations in ascitic fluid and has demonstrated infection resolution rates of 69–98%, with comparable efficacy between 5-day and 10-day treatment regimens [
204,
214]. Intravenous ceftriaxone has shown infection resolution rates of 73–100%, with efficacy similar to that of cefotaxime [
204]. Treatment with amoxicillin–clavulanic acid or ciprofloxacin also resulted in infection resolution and survival rates comparable to those of cefotaxime [
215,
216]. Oral ofloxacin demonstrated comparable efficacy to cefotaxime in carefully selected patients without gastrointestinal bleeding, renal dysfunction, hepatic encephalopathy, ileus, or shock [
217].
In a Korean multicenter randomized controlled trial involving 261 patients with SBP, infection resolution rates at 120 hours were similar among cefotaxime (67.8%), ceftriaxone (77.0%), and ciprofloxacin (73.6%), with no significant difference in 1-month mortality among the three groups [
204]. A network meta-analysis including 12 studies and 1,278 patients with SBP showed that cefotaxime and ciprofloxacin had infection resolution rates (HR 0.90, 95% credible interval [CrI] 0.42–1.86 and HR 0.93, 95% CrI 0.69–1.25, respectively) and overall mortality (HR 0.56, 95% CrI 0.11–2.28 and HR 0.65, 95% CrI 0.12–2.72, respectively) comparable to those of ceftriaxone [
216].
However, resistance to quinolones among causative organisms of community-acquired SBP has increased over time; therefore, quinolones are not recommended as first-line empirical therapy and should be used only when susceptibility of the isolated organism is confirmed. In a Korean study, the overall quinolone resistance rate among SBP isolates was 18.3%, and resistance among
E. coli isolates reached 31.7% [
204,
212]. Accordingly, empirical therapy with intravenous cefotaxime (2 g every 6–8 hours) or ceftriaxone (1 g every 12 hours or 2 g once daily) for 5–7 days is recommended, with treatment duration individualized according to the patient’s clinical response. Randomized trials demonstrated that 5-day treatment with third-generation cephalosporins resulted in mortality, SBP resolution, and recurrence rates comparable to those of 10-day treatment [
218]. In a small prospective study, treatment response was assessed by repeat paracentesis, with a mean antibiotic duration of 4.8 days; treatment duration was not associated with mortality [
219].
Nevertheless, increasing antimicrobial resistance has led to higher failure rates of empirical cephalosporin-based therapy [
220]. According to the Study for Monitoring Antimicrobial Resistance Trends (SMART), the prevalence of extended-spectrum beta-lactamase (ESBL)-producing
E. coli and
K. pneumoniae isolated from intra-abdominal infections in Korea between 2002 and 2010 was 25.9% and 24.5%, respectively, which is higher than that reported in Europe or North America [
221]. In a multicenter retrospective Korean study conducted between 2016 and 2018, susceptibility to third-generation cephalosporins was only 61.4% for
E. coli and 80.7% for
Klebsiella species [
222]. However, studies focusing on community-acquired SBP in Korea reported relatively lower resistance rates to third-generation cephalosporins (1.6–10.7%) [
204,
205,
208]. Selection of empirical antibiotics should therefore consider the most common causative organisms and their local resistance patterns. In regions with a high prevalence of multidrug-resistant organisms, broader-spectrum antibiotics such as piperacillin/tazobactam may be considered for empirical treatment of community-acquired SBP [
222].
Recommendations
1. Community-acquired spontaneous bacterial peritonitis should be treated empirically with intravenous third-generation cephalosporins (ceftriaxone or cefotaxime) for 5–7 days. (A1)
2. In regions with a high prevalence of multidrug-resistant organisms, broader-spectrum antibiotics such as piperacillin/tazobactam may be considered for empirical treatment of community-acquired spontaneous bacterial peritonitis. (B1)
Hospital-acquired and healthcare-associated spontaneous bacterial peritonitis
Hospital-acquired and healthcare-associated SBP are closely associated with infection caused by multidrug-resistant organisms (MDROs) [
192]. Infections caused by MDROs—defined as organisms non-susceptible to at least one agent in three or more antimicrobial categories—have been increasing in healthcare settings [
223]. Patients with decompensated cirrhosis are particularly vulnerable to MDRO infections due to repeated hospitalizations, frequent invasive procedures, and repeated exposure to prophylactic or therapeutic antibiotics. In a prospective study of 2,029 patients with decompensated cirrhosis, 30–38% of infections were caused by MDROs [
224]. In a multinational prospective study including 1,302 cirrhotic patients with bacterial or fungal infections, the prevalence of MDRO infections was 25% overall and was highest in Asia (50%) [
225]. Hospital-acquired infection was an independent risk factor for both MDRO infection and 28-day mortality (sub-distribution HR 1.35).
In Korean studies, ESBL-producing organisms accounted for 1.6–40% of SBP cases, with lower rates in community-acquired infection (1.6–10.7%) and higher rates when hospital-acquired cases were included (6–40%) [
204,
205,
207,
211]. Moreover, SBP caused by multidrug-resistant Gram-positive organisms, such as vancomycin-resistant
Enterococcus (VRE) and methicillin-resistant
Staphylococcus aureus (MRSA), has also been reported [
207].
In a Spanish retrospective study of 506 patients with SBP, hospital-acquired SBP was associated with approximately twice the 30-day mortality of community-acquired SBP (adjusted HR 1.966, 95% CI 1.181–3.272) and 2.5-fold higher risk of infection with third-generation cephalosporin-resistant organisms (adjusted HR 2.544, 95% CI 1.194–5.422) [
236]. Similarly, in a Korean retrospective study of 236 patients, hospital-acquired SBP was associated with 2.18-fold higher 30-day mortality and 7.02-fold higher risk of third-generation cephalosporin-resistant infection compared with community-acquired SBP [
211]. Another Korean study also showed significantly higher 6-month mortality in hospital-acquired SBP than in community-acquired SBP (47% vs. 26%), along with higher rates of cefotaxime resistance, ESBL production, and ciprofloxacin resistance [
213].
Empirical antibiotic selection for hospital-acquired SBP should consider infection severity, local antimicrobial resistance patterns, and patient-specific risk factors. Piperacillin/tazobactam is recommended as a first-line empirical therapy for healthcare-associated or hospital-acquired SBP in regions with a low prevalence of MDROs. However, in the aforementioned multinational study, antibiotic susceptibility among infected cirrhotic patients in Asia was only 48% for third-generation cephalosporins, 48% for piperacillin/tazobactam, and 71% for carbapenems [
225]. In a study of 86 patients with SBP, resistance rates for quinolones (50% vs. 18%), piperacillin/tazobactam (30% vs. 11%), and third-generation cephalosporins (30% vs. 33%) were observed in hospital-acquired infections and healthcare-associated infections, while carbapenem resistance was not observed [
192,
227].
In a randomized controlled trial of 32 patients with hospital-acquired SBP, combination therapy with meropenem (1 g every 8 hours) plus daptomycin (6 mg/kg/day) achieved a significantly higher infection resolution rate within 7 days than ceftazidime monotherapy (86.7% vs. 25%), although 90-day transplant-free survival was similar. Failure of initial antibiotic therapy was strongly associated with increased mortality (HR 20.6) [
192]. In a Korean retrospective study comparing carbapenem (n=95) and third-generation cephalosporin (n=655) therapy, in-hospital mortality did not differ overall; however, in patients with high disease severity (CLIF-SOFA ≥7), mortality was significantly lower in the carbapenem group [
208].
Accordingly, in patients at high risk for MDRO infection— such as those with hospital-acquired or healthcare-associated infection, severe infection, prolonged prophylactic antibiotic use, recent beta-lactam exposure, recent hospitalization, or immunosuppression—initial therapy with meropenem alone or in combination with a glycopeptide should be considered. In a study of 635 cirrhotic patients admitted with septic shock, inappropriate initial antibiotic therapy, delayed administration of appropriate antibiotics, and use of monotherapy were all independently associated with increased mortality [
203]. Early administration of appropriate antibiotics is therefore critical to improve infection resolution and survival.
In patients with a history of MRSA infection or positive MRSA screening, vancomycin should be added; in those with a history of VRE infection or positive VRE screening, daptomycin should be considered [
228]. If there is a history of recent piperacillin/tazobactam use, meropenem should be selected, and a glycopeptide (vancomycin or teicoplanin) may be added if necessary. However, because broad-spectrum antibiotic use promotes antimicrobial resistance, antibiotic stewardship principles should be followed: once culture results are available, antibiotic therapy should be de-escalated as early as possible and treatment duration minimized.
Areas requiring further research
Although empirical antibiotic therapy has improved outcomes in SBP, several unmet needs remain. The increasing prevalence of ESBL-producing Enterobacterales, MRSA, VRE, and carbapenem-resistant organisms is progressively limiting the effectiveness of standard empirical regimens. Although antibiotic selection based on regional resistance patterns is essential, real-time surveillance systems capable of guiding early empirical therapy are lacking. Moreover, large randomized trials directly comparing piperacillin/tazobactam, carbapenems, and combination regimens in high-risk or critically ill patients are insufficient.
Recommendations
1. In patients with spontaneous bacterial peritonitis at high risk for multidrug-resistant organisms including hospital-acquired infections, healthcare-associated infections, severe infections, prolonged prophylactic antibiotic use, recent beta-lactam exposure, recent hospitalization, or immunosuppression, broader-spectrum antibiotics such as piperacillin/tazobactam or carbapenems should be considered for initial therapy. (B1)
Assessment of treatment response
Failure of empirical antibiotic therapy is associated with increased mortality; therefore, diagnostic paracentesis is recommended 48 hours after initiation of antibiotic therapy to assess treatment response [
220]. However, if the causative organism has been identified, susceptibility to the administered antibiotic is confirmed, and the patient shows clear clinical improvement, repeat paracentesis is not required. Treatment failure is defined as the failure to achieve a reduction of at least 25% in ascitic PMN count compared with baseline after 48 hours of antibiotic therapy [
193]. This finding suggests infection with antibiotic-resistant organisms and warrants modification of antimicrobial therapy and evaluation for secondary bacterial peritonitis using abdominal imaging.
When treatment failure is suspected or antibiotic adjustment is required, therapeutic decisions should be individualized based on culture and susceptibility results, with careful consideration of the risk of resistant organisms and the need for combination therapy. Consultation with infectious disease specialists is recommended in such situations. In cases of treatment failure, antibiotics should be modified to target ESBL-producing organisms,
MRSA, Enterococcus species, or
Pseudomonas aeruginosa as appropriate. Infections caused by carbapenemase-producing or carbapenem-resistant
Enterobacterales can be treated with tigecycline monotherapy or high-dose tigecycline combined with prolonged-infusion carbapenems; in severe infections, adjunctive intravenous colistin should be considered [
229]. Severe infections caused by
Pseudomonas species resistant to both carbapenems and quinolones require combination therapy with intravenous amikacin or tobramycin plus a carbapenem or ceftazidime. VRE infections should be treated with linezolid, daptomycin, or tigecycline [
230]. Because these agents are associated with a high risk of nephrotoxicity in patients with cirrhosis, serum drug levels should be carefully monitored, particularly when aminoglycosides or vancomycin are used.
Recommendations
1. Treatment response should be assessed by repeat paracentesis between 48 and 72 hours after initiation of empirical antibiotic therapy. If there is no significant decrease (≥25%) in ascitic PMN count or if clinical deterioration occurs, broader-spectrum antibiotics should be used and secondary bacterial peritonitis should be excluded. (B1)
Other treatments
Albumin
Renal dysfunction develops in approximately 30–40% of patients with SBP [
231], and is associated with very high mortality [
232]. Because AKI is closely associated with in-hospital mortality, renal function should be monitored carefully in all patients with SBP. In cirrhosis complicated by infection, albumin plays important roles beyond simple intravascular volume expansion. In a randomized controlled trial involving 126 patients with SBP, combination therapy with intravenous cefotaxime and albumin (1.5 g/kg at diagnosis and 1.0 g/kg on day 3) significantly reduced the incidence of hepatorenal syndrome (10% vs. 33%) and mortality (10% vs. 29%) compared with cefotaxime alone [
99]. The benefit of albumin was most pronounced in patients with baseline serum bilirubin ≥4 mg/dL or serum creatinine ≥1 mg/dL; in contrast, among patients with bilirubin <4 mg/dL and creatinine <1 mg/dL, the incidence of hepatorenal syndrome was low, and there was no clear benefit of albumin.
The Guideline Revision Committee performed a systematic review and meta-analysis of the effects of albumin in SBP, including nine studies (
Supplementary Material 3). Albumin significantly reduced overall mortality compared with placebo (risk ratio 0.49, 95% CI 0.32–0.75) and the risk of AKI (risk ratio 0.28, 95% CI 0.15–0.51). Accordingly, intravenous albumin in combination with antibiotics is recommended in patients with SBP to reduce the risk of mortality and AKI.
Primary prophylaxis
In cirrhotic patients with gastrointestinal bleeding, bacterial infections including SBP occur in approximately 35–66% of cases within 1–2 weeks of hospitalization [
233]. Even in current clinical practice where antibiotic prophylaxis is routinely used, approximately 20% of patients with cirrhosis and acute variceal bleeding develop bacterial infections during their initial hospitalization period (median, 3 days) [
234]. In these patients, infection increases the risk of hemostatic failure, rebleeding, and mortality [
235,
236]. Administration of oral norfloxacin 400 mg twice daily for 7 days has been shown to effectively prevent infections in cirrhotic patients with gastrointestinal bleeding [
237]. However, the proportion of strains resistant to quinolones is increasing [
212,
238], and in patients with advanced hepatic impairment (the presence of at least two of the following: ascites, severe malnutrition, bilirubin >3 mg/dL, hepatic encephalopathy) accompanied by gastrointestinal bleeding, ceftriaxone 1 g daily for 7 days demonstrated superior efficacy in preventing infection compared with oral norfloxacin [
239]. Therefore, intravenous ceftriaxone is currently recommended as the standard prophylaxis. A meta-analysis demonstrated that prophylactic antibiotic therapy in cirrhotic patients with gastrointestinal bleeding significantly reduced the incidence of severe bacterial infections, rebleeding, and mortality [
240,
241].
Nevertheless, advances in the management of gastrointestinal bleeding in cirrhosis—including endoscopic hemostasis, vasoconstrictors, restricted transfusion strategies, and TIPS—as well as concerns regarding the emergence of antibiotic-resistant organisms, have weakened the evidence supporting routine 7-day antibiotic prophylaxis in all patients. In particular, a randomized controlled trial involving patients with Child–Pugh class A cirrhosis showed that the non-prophylaxis group was non-inferior to the prophylaxis group with respect to infection and mortality [
242]. Another non-inferiority trial demonstrated that a short 2-day course of antibiotics was not inferior to a 5-day course [
243]. In a recent meta-analysis including 14 randomized controlled trials, antibiotic prophylaxis maintained its protective effect against infection, but the reduction in mortality was not statistically significant, and this trend was more pronounced in recent studies [
244].
Among patients with cirrhosis and ascites, those with a low ascitic fluid protein concentration are at increased risk of SBP [
245]. In patients with an ascitic protein concentration ≤1.5 g/dL accompanied by signs of liver failure (Child–Pugh score ≥9 and serum bilirubin ≥3 mg/dL), renal dysfunction (serum creatinine ≥1.2 mg/dL or blood urea nitrogen ≥25 mg/dL), or hyponatremia (serum sodium <130 mmol/L), prophylactic administration of norfloxacin 400 mg/ day for one year reduced the incidence of SBP, hepatorenal syndrome, and mortality [
246]. Therefore, in patients with an ascitic protein concentration ≤1.5 g/dL, particularly those with concomitant liver failure, renal dysfunction, or hyponatremia, prophylactic norfloxacin 400 mg/day may be beneficial. In addition to norfloxacin, rifaximin and trimethoprim–sulfamethoxazole have also shown some efficacy in preventing SBP [
247,
248]. In a retrospective study of cirrhotic patients without a history of SBP, rifaximin used as primary prophylaxis significantly reduced the incidence of SBP (adjusted HR 0.28;
P=0.007) [
249], and a prospective controlled study also demonstrated a significantly lower incidence of SBP with rifaximin compared with control (4.5% vs. 46%,
P=0.027) [
250]. A Korean retrospective study involving patients treated with rifaximin for hepatic encephalopathy also showed a significant reduction in SBP incidence (
P<0.001) [
251]. In a recently published multicenter randomized controlled trial involving patients with ascitic protein ≤1.5 g/dL, rifaximin did not significantly improve 12-month survival or reduce the overall risk of cirrhosis-related complications compared with placebo; however, in a per-protocol analysis limited to patients with good adherence, rifaximin significantly reduced the risk of complications, including SBP [
248].
In addition to prophylactic antibiotics, albumin administration may help reduce the risk of new-onset infections, including SBP. According to a systematic review and meta-analysis conducted by the Guideline Revision Committee involving 12 studies of cirrhotic patients with ascites, albumin administration significantly reduced the risk of new infections (risk ratio 0.42, 95% CI 0.25–0.70) and SBP (risk ratio 0.36, 95% CI 0.17–0.74) compared with placebo (
Supplementary Material 3). Therefore, in high-risk cirrhotic patients with ascites, combined use of prophylactic antibiotics and albumin may help prevent infections including SBP and improve clinical outcomes. Further studies are needed to define optimal patient selection and treatment protocols.
Secondary prophylaxis
Since patients who recover from an episode of SBP are at high risk of recurrence, with reported 1-year recurrence rates of approximately 40–70% [
252,
253], a number of studies have evaluated antibiotic therapy to reduce the risk of recurrence. In patients who recovered from SBP, administration of norfloxacin 400 mg/day reduced the recurrence rate from 68% to 20%, and recurrence caused by Gram-negative bacteria decreased from 60% to 3% [
254]. Similar to primary prophylaxis, rifaximin has also shown some efficacy in secondary prophylaxis of SBP [
255,
256]. In a recent single-center randomized controlled trial, rifaximin showed no significant difference from norfloxacin in terms of primary prevention of SBP; however, during 6 months of follow-up, rifaximin significantly reduced SBP recurrence compared with norfloxacin (7% vs. 39%,
P=0.004) [
255].
The Guideline Revision Committee conducted a systematic review and network meta-analysis to compare the effectiveness of different agents for primary and secondary prophylaxis of SBP, including a total of 27 randomized controlled trials (
Supplementary Material 5). Compared with placebo, the risk ratios of SBP were 0.55 (95% CI 0.33–0.91) for norfloxacin and 0.32 (95% CI 0.19–0.54) for rifaximin, indicating superior preventive efficacy with rifaximin. Rifaximin (risk ratio 0.49, 95% CI 0.32–0.76) was also associated with lower mortality compared with norfloxacin (risk ratio 0.68, 95% CI 0.50–0.93), ciprofloxacin (risk ratio 0.65, 95% CI 0.39–1.09), and trimethoprim–sulfamethoxazole (risk ratio 0.50, 95% CI 0.24–1.03). Based on these findings, prophylactic administration of rifaximin or norfloxacin may be considered in patients at high risk of SBP or in those who have recovered from SBP.
However, important limitations of long-term prophylactic antibiotic therapy must be considered, and routine use in all patients may not be appropriate. In a prospective study, 67% of SBP episodes that occurred during prophylaxis were caused by quinolone-resistant organisms, and approximately 40% were due to multidrug-resistant organisms [
257]. In a large retrospective cohort study from the United States, patients who received primary prophylaxis had more than two-fold higher risk of multidrug-resistant infections than those who did not [
258]. Similarly, patients receiving secondary prophylaxis had 63–68% higher risk of SBP recurrence within two years compared with those who did not receive prophylaxis [
259]. Randomized controlled trials supporting the use of prophylactic antibiotics for SBP are generally based on small and heterogeneous populations, leading to uncertainty in the estimation of their effectiveness [
260].
Areas requiring further research
In low-risk patients with well-preserved liver function, recent evidence suggests that the duration of prophylactic antibiotics during gastrointestinal bleeding may be shortened or omitted. Additional studies are required to define risk-stratified strategies and optimal treatment duration.
Although recent data suggesting the limitations of prophylactic antibiotics are largely based on retrospective analyses, the clinical benefit of long-term antibiotic prophylaxis for SBP may no longer be as clear as in the past [
261–
263]. Therefore, antibiotic prophylaxis for primary and secondary prevention of SBP should be restricted to select high-risk patients, and large, well-designed randomized controlled trials are needed to reassess its benefit in the current clinical setting.
Recommendations
1. In cirrhotic patients with gastrointestinal bleeding, intravenous ceftriaxone 1 g/day is recommended to prevent infections, including spontaneous bacterial peritonitis. (A1)
2. In patients with ascitic protein concentration ≤1.5 g/ dL accompanied by severe liver failure, renal dysfunction, or hyponatremia, or in patients who have recovered from spontaneous bacterial peritonitis, prophylactic administration of rifaximin or norfloxacin should be considered to prevent spontaneous bacterial peritonitis. (A2)
ACUTE KIDNEY INJURY AND HEPATORENAL SYNDROME
Definition and diagnostic criteria
AKI is a common complication of cirrhosis, occurring in approximately 13–20% of patients hospitalized with decompensated cirrhosis [
264,
265]. The development of AKI is closely associated with poor prognosis in these patients [
232,
266,
267], and both the occurrence and progression of AKI are independent predictors of mortality in cirrhosis [
267,
268]. Even after apparent recovery from AKI, renal function often declines progressively, and outcomes remain worse compared with patients who never develop AKI [
269]. Inadequate treatment of AKI or failure to respond to therapy may lead to progression to hepatorenal syndrome (HRS) [
270]. The prognosis of HRS is extremely poor, with a median survival of less than 3 months [
271,
272]. Liver transplantation is the only treatment shown to improve long-term survival in patients with HRS; however, impaired renal function before transplantation adversely affects post-transplant survival and increases postoperative complications [
273]. While the 3-year post-transplant survival rate approaches 80% in those without HRS, it is approximately 60% in those with HRS, and the need for post-transplant dialysis is more frequent [
274]. Therefore, improvement of renal function before liver transplantation is critically important.
Diagnostic criteria
Acute kidney injury
The traditional definition of AKI was based on changes in serum creatinine (sCr), defined as an increase of ≥50% from baseline to a level exceeding 1.5 mg/dL [
109,
275]. However, the use of sCr to assess renal function in patients with cirrhosis has several limitations. In cirrhosis, reduced muscle mass leads to decreased creatinine production from creatine [
276,
277], tubular secretion of creatinine is increased [
278], and elevated serum bilirubin levels may artifactually lower measured sCr values [
279]. As a result, renal function may appear better than it actually is when assessed solely by sCr [
280]. In addition, reliance on a single threshold value (1.5 mg/dL) without considering short-term changes over days or weeks makes it difficult to distinguish acute from chronic kidney injury [
281].
To address these limitations, the diagnostic criteria for AKI have evolved over time. In 2004, the ADQI proposed the RIFLE (Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease) criteria, which classified AKI into three stages based on changes in sCr and urine output [
282]. In 2007, the Acute Kidney Injury Network (AKIN) criteria incorporated small changes in sCr within 48 hours [
283]. In 2012, the Kidney Disease Improving Global Outcomes (KDIGO) guidelines combined the RIFLE and AKIN criteria and defined AKI as an increase in sCr by ≥0.3 mg/dL within 48 hours, an increase of ≥50% within 7 days, or urine output <0.5 mL/kg/h for at least 6 hours [
284].
In 2015, the International Club of Ascites (ICA) excluded urine output from the diagnostic criteria for AKI in cirrhosis, because the RIFLE, AKIN, and KDIGO criteria were not developed specifically for cirrhotic patients. In cirrhosis, urine output may decrease even in the absence of renal dysfunction, and diuretic use or dose escalation can alter urine output without true changes in renal function, potentially leading to misclassification [
269].
However, recent studies have shown that reduced urine output is a sensitive early indicator of AKI in patients with cirrhosis and is strongly associated with prognosis in critically ill patients [
285,
286]. Accordingly, the 2024 ADQI-ICA consensus reintroduced urine output into the diagnostic criteria of AKI in cirrhotic patients. AKI is now defined as an increase in serum creatinine ≥ 0.3 mg/dL within 48 hours or ≥ 50% from baseline value known or presumed to have occurred within the prior 7 days, and/or urine output ≤0.5 mL/ kg for ≥ 6 hours (
Table 7) [
110].
Whenever possible, baseline sCr used to diagnose AKI should be obtained from values measured within the previous 3 months. When multiple prior sCr values are available, use of the median value reduces bias [
110]. If no sCr measurement is available within the previous 3 months, the most recent value up to 12 months prior may be used to distinguish acute from chronic kidney disease. In the absence of any prior measurement, sCr on admission may be used as the baseline [
281].
Hepatorenal syndrome
In advanced cirrhosis, progressive systemic and splanchnic vasodilation leads to a reduction in effective arterial blood volume, with subsequent activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system. This results in reduced renal perfusion and intense renal vasoconstriction, leading to HRS, which does not improve despite adequate volume expansion. Although HRS is classified as a functional renal disorder, various degrees of structural injury involving glomerular, renovascular, and tubular injury may coexist, and chronic damage may also be present [
287].
The diagnostic criteria for HRS have also evolved over time. The ICA first proposed diagnostic criteria in 1996 [
109]. The diagnostic criteria for HRS, revised in 2007, are as follows: 1) Creatinine clearance was excluded because its measurement method is complex and its accuracy in measuring renal function is low. 2) Renal failure occurring in the presence of bacterial infection was included. 3) Plasma volume expansion is achieved through intravenous albumin administration rather than saline. 4) Additional criteria from the previous diagnostic criteria were removed due to low sensitivity and specificity of the test. However, the revised criteria in 2007 still require a doubling of sCr to 2.5 mg/dL or higher within 2 weeks as a diagnostic criterion for HRS [
270]. This has led to concerns that initiating vasoconstrictors such as terlipressin and albumin therapy, which are expected to restore renal function in HRS, may be too late. A study suggesting that higher sCr at the start of treatment for HRS was associated with lower therapeutic response supports this view [
288,
289].
Accordingly, in 2015, ICA abolished the sCr threshold and established the following diagnostic criteria for HRS: patients with cirrhosis and ascites who meet the criteria for AKI and do not respond to 2 days of diuretic discontinuation and plasma volume expansion (1 g of albumin per kg of body weight, up to a maximum of 100 g). Vasopressors and albumin therapy should be started regardless of absolute sCr value, allowing for earlier initiation of vasopressor and albumin therapy [
281].
Subsequent RCTs comparing albumin with crystalloid solutions for plasma expansion showed no significant differences in 30- or 90-day mortality, and increased risk of pulmonary edema was observed in the albumin group [
290,
291]. In particular, patients with euvolemic or hypervolemic conditions were advised to exercise caution as excessive albumin administration may increase the risk of pulmonary edema [
291].
In this regard, the 2024 ADQI-ICA consensus allows the use of crystalloid solutions as well as albumin for plasma expansion and recommends shortening the volume expansion period to 1 day, as a 2-day requirement may delay initiation of vasoconstrictor therapy [
110].
In addition, the intravascular volume status of the patient should be evaluated first, and for patients with hypovolemia, adequate volume expansion should be performed for 1 day. When volume status is equivocal and/or difficult to assess, fluid challenge (250–500 mL of crystalloid or 1–1.5 g/kg of 20–25% albumin) may be performed to exclude any reduction in intravascular volume as the cause of AKI, and, if there is no improvement in sCr and/or urine output within 24 hours, a diagnosis of HRS AKI should be considered [
110].
Nevertheless, a recent RCT reported that even when a 2-day volume expansion period was applied according to the 2015 ICA criteria, initiation of terlipressin was not significantly delayed [
292]. Until further evidence becomes available, HRS should be diagnosed in patients with cirrhosis and ascites who meet AKI criteria and show no improvement after 1–2 days of appropriate volume expansion with albumin (1 g/kg/day, maximum 100 g) or crystalloid solutions, after exclusion of other causes of renal dysfunction (
Table 8). Careful monitoring for volume overload and pulmonary edema is required during albumin administration.
With regard to adequate volume resuscitation, 30 mL/kg of crystalloid fluid was administered for the first 3 hours to evaluate responsiveness in a prospective randomized controlled trial of patients with cirrhosis and sepsis-induced hypotension [
291]. Although not limited to cirrhotic patients, a prospective study in critically ill patients with AKI compared outcomes after administration of 1,000–3,500 mL of crystalloid fluids within the first 24 hours [
293]. The rate and volume of fluid administration should be individualized based on hemodynamic status, volume status, and cardiac function, with careful reassessment after treatment.
Meanwhile, in order to evaluate patient’s volume status and treatment responsiveness according to fluid challenge, a comprehensive approach is required, including history taking, physical examination, static measurements such as central venous pressure and pulmonary artery pressure, dynamic measurements such as changes in cardiac stroke volume and pulse pressure, and results of point-of-care ultrasonography at the bedside [
294]. Caution is needed in patients with cirrhosis and ascites, as central venous pressure measurements may be inaccurate if intra-abdominal pressure is increased due to ascites.
Regarding classification, the 1996 ICA criteria distinguished type 1 HRS (characterized by rapid deterioration within 2 weeks) from type 2 HRS (characterized by more gradual progression over >2 weeks with moderate renal dysfunction [sCr 1.5–2.5 mg/dL], typically in patients with refractory ascites) [
109]. Afterwards, in the diagnosis of HRS by ICA in 2015, the need for absolute sCr value (1.5 mg/dL) for diagnosis was eliminated, and all cases were classified as HRS without subtype classification in accordance with updated diagnostic guidelines that require AKI to precede the diagnosis [
281]. In 2024, ADQI-ICA suggested using the terms HRS-AKI, HRS-AKD (acute kidney disease), or HRSCKD (chronic kidney disease) depending on the timing and duration of renal dysfunction. In this framwork, HRS lasting less than 90 days is classified as HRS-AKD, HRS lasting more than 90 days is classified as HRS-CKD, and HRSAKD patients who meet the criteria for AKI are classified as HRS-AKI [
110].
Approximately 30% of AKI cases in cirrhosis are due to structural kidney injury, including glomerulopathies commonly seen in viral hepatitis and acute tubular necrosis (ATN). ATN may result from gastrointestinal bleeding, excessive diuretic use, relative hypotension following LVP, or exposure to nephrotoxic agents such as antibiotics, nonsteroidal anti-inflammatory drugs, and iodinated contrast media [
295,
296]. Postrenal AKI due to urinary tract obstruction should also be considered, although it accounts for less than 1% of AKI cases in cirrhosis [
297]. These alternative primary causes of AKI must be excluded when diagnosing HRS.
Pathophysiology
In patients with cirrhosis, AKI can be broadly categorized into prerenal AKI, acute tubular necrosis, and hepatorenal syndrome. Approximately 70% of AKI cases are functional in nature and are caused by reduced renal perfusion due to gastrointestinal bleeding, bacterial infection, excessive diuretic use, LVP, diarrhea induced by non-absorbable disaccharides (e.g., lactulose), or hypotension related to nonselective beta-blockers [
295]. Functional AKI is primarily driven by a reduction in effective arterial blood volume, a shared mechanism underlying many complications of cirrhosis. Splanchnic and systemic vasodilation associated with cirrhosis and portal hypertension leads to decreased effective arterial blood volume, triggering activation of vasoconstrictor systems such as the sympathetic nervous system and the renin–angiotensin–aldosterone system. This cascade promotes sodium and water retention, ascites formation, and hyponatremia, ultimately reducing renal perfusion and causing renal dysfunction [
298]. As the process progresses, intense renal vasoconstriction may culminate in hepatorenal syndrome [
299–
301]. Approximately 70% of patients with functional AKI have prerenal azotemia, which is reversible with adequate volume resuscitation, whereas the remaining 30% are diagnosed with hepatorenal syndrome [
302].
HRS represents the most severe form of AKI in cirrhosis and is characterized by persistent renal hypoperfusion and intense renal vasoconstriction that do not respond to adequate volume expansion. Inflammatory cytokines, vasodilatory mediators, reactive oxygen species, and relative reductions in cardiac output may further exacerbate renal hypoperfusion and increase the risk of HRS [
300,
303–
306]. In addition, excessive bile acids may exert direct toxic effects on tubular epithelial cells [
307].
Differential diagnosis and biomarkers
Differentiating among prerenal AKI, ATN, and HRS in cirrhosis relies on careful assessment of clinical history, physical examination, and laboratory evaluation, including urinary indices such as fractional excretion of sodium (FENa), fractional excretion of urea (FEUrea), and urinary sodium concentration [
308].
In cirrhosis, FENa may be <1% even in the absence of AKI, leading to its exclusion from the diagnostic criteria for HRS. However, lowering the FENa cutoff to <0.1–0.2% and combining it with other urinary biomarkers has been shown to improve diagnostic specificity for HRS [
309,
310]. Unlike sodium, urea is primarily reabsorbed in the proximal tubule and is not affected by diuretics acting on the loop of Henle or distal tubules. FEUrea has demonstrated excellent diagnostic performance in differentiating ATN from other causes of AKI, with an area under the ROC curve of 0.96 and sensitivity and specificity of 85% and 100%, respectively, at a cutoff value of 33.4 [
311,
312].
Despite these advances, distinguishing ATN from HRS remains challenging, as these conditions may coexist or share features of both functional and structural injury. To improve differentiation, numerous biomarkers have been developed and evaluated [
313,
314].
Cystatin C is a low-molecular-weight protein produced by all nucleated cells and cleared primarily by glomerular filtration. In cirrhosis, serum cystatin C often rises approximately 48 hours earlier than sCr, enabling earlier detection of AKI. It is less influenced by age and diabetes and may provide a more accurate estimate of glomerular filtration rate [
315–
317]. In a Korean multicenter study, cystatin C was a stronger predictor of 3-month mortality (AUC 0.83) than creatinine (AUC 0.66) in patients with cirrhosis [
318]. However, most studies rely on single measurements, and variability in cutoff values limits its routine clinical application.
Tubular injury biomarkers include enzymes released during cell injury (e.g., N-acetyl-β-D-glucosaminidase, α-glutathione S-transferase), proteins upregulated in response to injury (e.g., Kidney Injury Molecule-1, Neutrophil Gelatinase-Associated Lipocalin [NGAL]), inflammatory markers such as interleukin-18, and plasma proteins with reduced tubular reabsorption (e.g., α1-microglobulin, β2-microglobulin, retinol-binding protein) [
319,
320]. In general, higher levels of these biomarkers suggest ATN. Among them, urinary NGAL is the most extensively studied and has shown excellent diagnostic accuracy for ATN, with reported AUC values ranging from 0.65 to 0.97 (
Table 9) [
320–
332].
Urinary NGAL levels of 220–250 μg/g creatinine are more suggestive of ATN than prerenal AKI or HRS. Recent studies have also shown that urinary NGAL <220 μg/g creatinine is associated with a higher response rate to terlipressin therapy (70% vs. 33% when ≥220 μg/g), suggesting a role in predicting treatment response and mortality in HRS [
324,
325]. The Guideline Revision Committee performed a meta-analysis including 22 studies (
Supplementary Material 6), which demonstrated the excellent diagnostic performance of urinary NGAL in distinguishing ATN from non-ATN causes of AKI, with a pooled OR of 23.07 (95% CI 9.67–55.08;
P<0.0001). Higher urinary NGAL levels were also significantly associated with increased 90-day mortality (pooled HR 1.08, 95% CI 1.01–1.16;
P<0.0001).
Nevertheless, heterogeneity in measurement units and cutoff values, overlap between AKI subtypes, and the lack of kidney biopsy–confirmed diagnoses limit the clinical application of these biomarkers, highlighting the need for further validation.
Areas requiring further research
A consensus has not yet been reached regarding the optimal type and duration of plasma expansion for the diagnosis of HRS in cirrhosis. Large prospective studies are needed to establish standardized approaches. In addition, standardized methods for assessing volume status are required to minimize adverse effects while ensuring adequate plasma expansion. Prospective studies are also needed to define standardized diagnostic criteria and clinical applications for biomarkers in the diagnosis and differential diagnosis of AKI and HRS in cirrhosis.
Recommendations
1. AKI should be diagnosed in patients with cirrhosis when serum creatinine increases by ≥0.3 mg/dL within 48 hours, by ≥50% from baseline within 7 days (or presumed), and/or when urine output is <0.5 mL/ kg/h for at least 6 hours. (B1)
2. Hepatorenal syndrome should be diagnosed in patients with cirrhosis and ascites who meet AKI criteria and show no improvement after diuretic withdrawal and 1–2 days of adequate volume expansion with albumin (1 g/kg/day, maximum 100 g) or crystalloid solutions, after exclusion of other causes of AKI. (B1)
3. Biomarker testing, including serum cystatin C and urinary neutrophil gelatinase–associated lipocalin (NGAL), may be helpful for early diagnosis of AKI and for differentiating acute tubular necrosis from hepatorenal syndrome. (B1)
Treatment
General management of acute kidney injury
The therapeutic approach to AKI in patients with cirrhosis should be individualized according to the etiology of kidney injury, the presence of precipitating factors, the degree of dysfunction in other organs, and coexisting comorbidities. A systematic assessment to identify these factors should precede treatment initiation (
Fig. 2). In cases of functional kidney injury without structural parenchymal damage, renal function may improve after correction of the underlying cause. Therefore, potentially reversible precipitating factors should be identified and promptly corrected in the course of AKI. To exclude intrinsic renal injury, urinalysis should be performed to assess for proteinuria and hematuria. Potential nephrotoxic agents, including nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, vasodilators, and radiographic contrast media should be discontinued whenever possible or dose-adjusted if discontinuation is not feasible.
In patients with stage 1 AKI accompanied by effective arterial hypovolemia, intravascular volume should be actively restored using albumin, crystalloid solutions, or blood products. When bacterial infection is suspected, empiric antibiotic therapy should be initiated without delay (
Fig. 2) [
6,
35,
191]. Stage 1 AKI can be further subclassified into stage 1a (sCr <1.5 mg/dL) and stage 1b (sCr ≥1.5 mg/dL). Multiple studies have demonstrated that stage 1b AKI is associated with poorer outcomes than stage 1a, including increased short-term mortality, higher risk of AKI progression, and lower likelihood of renal recovery [
333–
336]. More recent studies have reported that even stage 1a AKI is associated with significantly increased mortality risk [
337]. Accordingly, close monitoring of kidney function and aggressive management of risk factors are required even in stage 1a, whereas stage 1b should be recognized as a high-risk condition warranting more intensive early intervention and monitoring.
If renal function does not recover despite these initial measures and AKI progresses to stage 2 or 3, or if patients present with stage 2 or 3 AKI at admission, diuretics should be discontinued and 20–25% albumin should be administered at a dose of 1 g/kg/day for 1–2 days. Evidence from critically ill populations, including patients with sepsis, suggests that crystalloid solutions used for initial resuscitation significantly reduce the risk of renal deterioration. Therefore, depending on the clinical context—such as the presence of sepsis, the risk of pulmonary edema, albumin availability, and contraindications—crystalloid resuscitation can be considered. In patients with prerenal AKI, renal function typically improves within 1–2 days after adequate volume expansion [
338]. If there is no response after 1–2 days of volume expansion and the clinical criteria for HRS are met, vasoconstrictor therapy, such as terlipressin, should be initiated in combination with albumin [
6,
35,
110,
191,
339].
Pharmacological treatment
Albumin
Albumin constitutes approximately 60% of total plasma protein and carries a net negative charge, enabling it to bind sodium ions and generate oncotic pressure that retains intravascular water [
340]. Accordingly, hemodynamic response to albumin administration may serve as a useful indicator of whether AKI is associated with effective arterial hypovolemia [
191,
332,
341]. Albumin also contains a free cysteine moiety (Cys-34), conferring antioxidant and scavenging properties that allow it to bind and neutralize proinflammatory cytokines, bacterial products, and reactive oxygen species [
342]. Albumin administration improves renal blood flow in patients with cirrhosis and acute decompensation complicated by AKI, partly through secondary attenuation of sympathetic nervous system activation [
343]. In patients with cirrhosis and AKI who fulfill the diagnostic criteria for HRS, combination therapy with vasoconstrictors such as terlipressin and 20–25% albumin (20–40 g/day) is recommended. Albumin monotherapy is generally insufficient to achieve HRS reversal [
339,
344]; however, its anti-inflammatory, antioxidant, immunomodulatory, endothelial-stabilizing, and renal perfusion–enhancing effects may potentiate the therapeutic efficacy of vasoconstrictors.
Although albumin administration is a cornerstone of AKI and HRS management, careful monitoring for adverse events is essential. The most common complication is circulatory and volume overload, which may manifest as pulmonary edema or peripheral edema due to rapid intravascular volume expansion. This risk is particularly high in patients with underlying heart failure or chronic lung disease. Allergic reactions such as fever, rash, or chills may occur in rare instances, and severe hypersensitivity reactions, including anaphylaxis, have been reported. Accordingly, albumin dosing should be individualized based on the patient’s volume status, and albumin administration should be discontinued if signs of pulmonary edema or fluid overload develop.
Vasoconstrictors
Terlipressin: Terlipressin is a synthetic vasopressin analogue that binds to V1 vasopressin receptors on vascular smooth muscle cells, thereby inducing vasoconstriction [
345]. In patients with cirrhosis, terlipressin selectively constricts dilated splanchnic vessels, redistributing blood flow to vital organs. This effect mitigates compensatory sympathetic nervous system activation and improves renal blood flow and perfusion [
346].
Prospective randomized controlled trials have demonstrated that combination therapy with terlipressin and albumin significantly improves renal function, with reported HRS reversal rates of approximately 24–27% [
344,
347]. In the CONFIRM trial, which compared terlipressin plus albumin with albumin alone in 300 patients with HRS, the HRS reversal rate was significantly higher in the combination therapy group (32% vs. 17%;
P=0.006), further supporting the clinical utility of terlipressin-based therapy [
339]. However, the impact of terlipressin on survival was inconsistent across studies. Several systematic reviews failed to demonstrate a significant survival benefit [
348,
349], whereas other meta-analyses suggested a potential reduction in short-term mortality [
350,
351].
The optimal dose and duration of terlipressin therapy have not been established. Conventionally, terlipressin is administered as an intravenous bolus at 1.0–2.0 mg every 6 hours, with reassessment every 24 hours. If sCr does not decrease by at least 25%, the dose may be increased up to 2 mg per administration. Continuous infusion may be initiated at 2 mg/day (0.08 mg/hour) and titrated according to treatment response to a maximum of 12 mg/day (0.5 mg/ hour) (
Table 10).
Adverse events associated with terlipressin have been reported in up to 30% of patients. In addition to gastrointestinal symptoms such as abdominal pain and diarrhea, serious complications including peripheral ischemia, hyponatremia, and cardiac arrhythmias may occur [
352]. In a comparative study of bolus administration versus continuous infusion, the incidence of adverse events was significantly lower with continuous infusion (35% vs. 62%), while overall treatment response rates were comparable between the two approaches [
353].
Treatment response is defined based on changes in AKI stage: non-response refers to no improvement in AKI stage; partial response refers to a decrease in AKI stage with sCr remaining ≥0.3 mg/dL above baseline; and complete response refers to a decrease in AKI stage with sCr returning to within 0.3 mg/dL of baseline (
Table 11). Predictors of HRS reversal include lower baseline international normalized ratio, lower MELD score, lower baseline sCr, and an increase in mean arterial pressure following terlipressin initiation [
288,
344,
347,
354]. Terlipressin should be discontinued when complete response is achieved, when the total treatment duration reaches 14 days, or when there is no response after 48–72 hours at the maximum dose. Therapy should also be discontinued in the event of serious adverse event, initiation of renal replacement therapy, or liver transplantation (
Table 10). After discontinuation, HRS recurrence has been reported in approximately 5–20% of patients, necessitating close clinical monitoring [
351].
Other pharmacological therapies
Norepinephrine is a systemic vasoconstrictor that increases mean arterial pressure and improves renal perfusion [
355]. Systematic reviews and meta-analyses comparing norepinephrine with terlipressin in patients with HRS have shown no significant difference in HRS reversal rate or short-term survival, while the incidence of adverse events was significantly lower with norepinephrine [
356,
357]. Combination therapy with norepinephrine and albumin has also been reported to be more effective than midodrine, octreotide, and albumin [
351]. Because norepinephrine requires continuous hemodynamic monitoring, its use is generally limited to the intensive care unit setting. In regions where terlipressin is available, norepinephrine is not considered a first-line therapy but may be used as an alternative when terlipressin cannot be administered. Norepinephrine is administered as a continuous infusion at 0.5–3.0 mg/hour, with dose adjustments every 4 hours to achieve an increase in mean arterial pressure of approximately 10 mmHg [
110].
Midodrine is an oral alpha-adrenergic agonist that increases mean arterial pressure [
358]. Combination therapy with midodrine, octreotide, and albumin has been shown to improve renal function in patients with HRS, with some studies reporting improved survival compared with no treatment [
359,
360]. However, randomized controlled trials have reported that the combination of midodrine and octreotide is less effective at improving renal function than terlipressin plus albumin [
361]. In addition, a systematic review demonstrated that terlipressin therapy was significantly superior to a combination of midodrine and octreotide in achieving recovery from hepatorenal syndrome (OR 10.0, 95% CI 1.5–50.0) [
351]. Therefore, this combination is not recommended as a first-line therapy in regions where terlipressin or norepinephrine is available, but may be considered as an alternative option when neither agent can be used. Midodrine is administered orally at 7.5–15 mg three times daily, titrated to achieve an increase in mean arterial pressure of approximately 15 mmHg. Octreotide is administered subcutaneously at 100–200 μg three times daily [
362].
Non-pharmacological treatment
Transjugular intrahepatic portosystemic shunt
In patients with HRS, TIPS may improve renal perfusion by reducing portal hypertension and thereby facilitate recovery from HRS. In selected patients, an associated survival benefit has been reported. According to a 2018 systematic review, improvement in renal function was observed in 93% of patients following TIPS, and short-term survival was improved; however, hepatic encephalopathy occurred in 49% of patients [
363]. Although evidence is limited, previous studies support the role of TIPS in improving renal function and serving as a bridge to liver transplantation [
364,
365]. Therefore, TIPS may be selectively considered for the treatment of HRS in patients with refractory ascites, provided there is no advanced liver failure or severe cardiopulmonary dysfunction.
The Guideline Revision Committee conducted a systematic review and meta-analysis evaluating the efficacy of TIPS in HRS (
Supplementary Material 7). A total of 16 studies including 206,058 patients were analyzed, comprising 6,557 patients in the TIPS group and 199,501 in the non-TIPS group. TIPS was associated with significant improvement in renal function, including a mean reduction in serum creatinine of 1.07 mg/dL and an increase in urine output of approximately 1,000 mL/day.
In-hospital mortality was reduced by approximately 50% in the TIPS group compared with controls (OR 0.50, 95% CI 0.33–0.77). Survival rates in the TIPS group were 85% at 3 months, 77% at 6 months, and 59% at 12 months. Collectively, these findings suggest that TIPS may be considered a therapeutic option that confers meaningful benefit in renal recovery and survival in carefully selected patients with HRS.
Nevertheless, TIPS increases the risk of hepatic encephalopathy and may induce systemic arterial vasodilation, leading to hypotension and a potential reduction in renal perfusion pressure. Moreover, most studies demonstrating benefit were conducted in highly selected populations with relatively preserved liver function, warranting caution in interpretation and application [
366,
367]. TIPS should therefore be avoided or used with extreme caution in high-risk patients, including those with active systemic infection, severe hepatic encephalopathy, advanced pulmonary hypertension or heart failure, marked hyperbilirubinemia, or high MELD scores.
Renal replacement therapy
In patients with cirrhosis who develop uremic symptoms, volume overload, refractory hyperkalemia, or metabolic acidosis despite optimal medical therapy, renal replacement therapy (RRT) may be considered. When intermittent hemodialysis is not feasible because of hemodynamic instability, bleeding risk, or effective hypovolemia, continuous RRT (CRRT) may be an alternative.
In a study of 102 liver transplant candidates with AKI who received RRT, including CRRT, approximately 30% either underwent liver transplantation or experienced clinical improvement [
368]. These findings suggest that RRT may serve as a bridge therapy to transplantation in selected patients with decompensated cirrhosis. However, RRT does not reverse the underlying pathophysiology of HRS, and survival benefit is limited in patients who are not candidates for liver transplantation [
369].
Liver transplantation
Liver transplantation is the only treatment proven to improve long-term survival in patients with hepatorenal syndrome [
6,
35,
191]. Pre-transplant renal dysfunction adversely affects post-transplant outcomes and complication rates [
274,
370]. Renal recovery after transplantation has been reported in approximately 50–75% of patients [
371,
372].
The duration of renal dysfunction prior to transplantation is a key predictor of post-transplant renal recovery. Patients who receive RRT for more than 14 days prior to transplantation have a substantially reduced likelihood of renal recovery, with the risk of non-recovery increasing by approximately 6% per additional day of RRT [
372]. Recent guidelines recommend consideration of simultaneous liver–kidney transplantation in patients receiving RRT for more than 4 weeks prior to transplantation [
373].
Patients who recover renal function after transplantation have excellent outcomes, with reported survival rates exceeding 90% at 6 months to 1 year [
372,
374]. In contrast, patients without renal recovery have a markedly lower 1-year survival rate of approximately 60% [
372]. Therefore, early referral for liver transplantation is strongly recommended in patients with HRS who do not respond to medical therapy. Renal recovery does not differ significantly between deceased-donor and living-donor liver transplantation.
Prevention
Prevention of renal dysfunction in patients with cirrhosis requires avoidance of effective arterial hypovolemia and attenuation of systemic vasodilation. Diuretics should be used cautiously, and the dose of non-absorbable disaccharides (e.g., lactulose) should be adjusted to prevent excessive diarrhea. To reduce the risk of acute tubular necrosis, aminoglycosides and NSAIDs should be avoided [
375].
Non-selective beta-blocker treatment should be tailored, as high doses or use in advanced liver failure may reduce cardiac output and renal perfusion. Albumin infusion after LVP reduces the risk of renal dysfunction [
376]. Similarly, albumin administration in SBP lowers the risk of HRS development [
99,
377].
Long-term rifaximin therapy has been associated with a lower incidence of AKI and HRS in patients with cirrhosis and ascites [
250,
378]. However, randomized controlled trials have shown that although rifaximin combined with lactulose improves outcomes of hepatic encephalopathy, it has not been shown to significantly reduce the incidence of HRS [
379].
Areas for future research
Despite advances in the management of AKI and HRS, significant knowledge gaps remain. Evidence regarding optimal dosing, duration, and discontinuation criteria for terlipressin and albumin therapy is limited, and survival benefits remain inconsistent across studies.
Although TIPS shows promise for improving renal function and short-term survival, most data are derived from retrospective studies with inherent selection bias. Future research should focus on optimizing pharmacologic treatment algorithms, developing validated prediction models for treatment response, and establishing standardized indications for TIPS.
Recommendations
1. In patients with hepatorenal syndrome, combination therapy with terlipressin and albumin should be initiated in the absence of contraindications, and early referral for liver transplantation should be considered. (A1)
2. In patients with hepatorenal syndrome who do not respond to optimal medical therapy, transjugular intrahepatic portosystemic shunt may be considered in carefully selected patients. (B2)
OTHER COMPLICATIONS OF CIRRHOTIC ASCITES
Hepatic hydrothorax
Hepatic hydrothorax refers to the accumulation of transudative pleural effusion in the pleural space in patients with portal hypertension, in the absence of underlying cardiopulmonary or pleural disease. It occurs in approximately 5–10% of patients with cirrhosis [
380].
Pathophysiology
Hepatic hydrothorax develops when ascitic fluid migrates from the peritoneal cavity into the pleural space through small defects in the diaphragm, driven by negative intrathoracic pressure [
381]. These diaphragmatic defects are typically less than 1 cm in diameter and are most commonly located in the right hemidiaphragm [
382]. Malnutrition associated with cirrhosis may contribute to thinning of the diaphragmatic musculature and formation of these defects [
383].
Clinical manifestations
Hepatic hydrothorax occurs predominantly on the right side (60–80%), followed by the left side (12–17%), and bilaterally (8–24%). In approximately 9% of cases, hydrothorax may develop in the absence of detectable ascites [
384,
385]. A serum–pleural fluid albumin gradient (SPAG) ≤1.1 g/dL or isolated left-sided pleural effusion without ascites should prompt consideration of alternative etiologies, including infection, tuberculosis, malignancy, pancreatitis, or cardiopulmonary disease [
386]. Although some patients remain asymptomatic and are diagnosed incidentally, the pleural cavity is a confined space, and even a small volume of pleural fluid (<500 mL) may cause symptoms. Common manifestations include cough, dyspnea, chest discomfort, hypoxemia, and, in severe cases, respiratory failure [
383]. Symptoms vary according to the volume and rate of fluid accumulation and the presence of underlying cardiopulmonary disease [
387].
Diagnosis
The presence of pleural effusion can be confirmed using radiologic examinations such as ultrasonography or chest radiography. Diagnostic thoracentesis should be performed at the time of initial diagnosis to determine the etiology, assess for infection, and relieve symptoms. Hepatic hydrothorax can be diagnosed when the following criteria are met: (1) SPAG >1.1 g/dL; (2) pleural fluid total protein <2.5 g/dL or pleural fluid/serum total protein ratio <0.5; (3) pleural fluid/ serum LDH ratio <0.6; and (4) polymorphonuclear leukocytes <250 cells/mm
3 [
385].
Spontaneous bacterial empyema is a serious infectious complication of hepatic hydrothorax that requires prompt antibiotic therapy; therefore, diagnostic thoracentesis is mandatory when infection of pleural fluid is suspected. The diagnosis is established in the absence of pneumonia on chest imaging when pleural fluid culture is positive with a PMN count >250/mm
3, or when the culture is negative with PMN >500/mm
3 [
388,
389]. Clinical manifestations range from fever and chest pain to worsening hepatic encephalopathy and renal dysfunction. The causative organisms are similar to those identified in SBP [
390,
391]. Spontaneous bacterial empyema occurs in 10–26% of patients with hepatic hydrothorax, and approximately half of cases are associated with SBP [
392].
Management
The development of hepatic hydrothorax indicates progression to decompensated liver disease and should prompt consideration of liver transplantation [
393,
394]. Initial management parallels that of ascites and includes sodium restriction and diuretic therapy. Therapeutic thoracentesis should be performed in patients with significant dyspnea. Although large-volume thoracentesis may be a safe option in asymptomatic patients when end-expiratory pleural pressure remains below 20 cmH
2O, drainage is generally limited to less than 1–1.5 L per day to reduce the risk of reexpansion pulmonary edema [
395]. Due to a lack of clinical data, the optimal volume, rate, and frequency of drainage remain undefined; therefore, treatment should be tailored to the individual patient [
396,
397]. Repeated thoracentesis may increase the risk of infection, bleeding, and protein loss [
398].
For refractory hepatic hydrothorax, TIPS is the most commonly employed second-line therapy, with reported response rates of 70–80% [
399–
404]. However, TIPS is generally contraindicated in patients with severe hepatic dysfunction, uncontrolled hepatic encephalopathy, right-sided heart failure, pulmonary hypertension, complete portal vein thrombosis, uncorrectable coagulopathy, uncontrolled systemic infection, or intrahepatic malignancy [
405]. Furthermore, advanced age (>60 years), Child–Pugh class C, pre-TIPS MELD score >15–25, sCr >2 mg/dL, and sepsis are associated with poor outcomes following TIPS; therefore, liver transplantation needs to be prioritized among these patients [
406–
408]. Lack of improvement in hydrothorax after TIPS is also associated with poor prognosis and warrants early transplant evaluation [
402].
Surgical closure of diaphragmatic defects can directly prevent the migration of ascites from the abdominal to the thoracic cavity. However, a study of 63 patients who underwent surgical repair revealed that the 20-month survival rate for those with decompensated cirrhosis (Child-Pugh class C) was 53%, significantly lower than the 80–85% observed in Child-Pugh class A or B groups [
407]. Therefore, in cases where TIPS is unfeasible or unsuccessful, surgical closure may be considered, provided that residual liver function is well-preserved [
410]. Indwelling pleural catheters can achieve clinical improvement in hepatic hydrothorax in 28–47% of cases, making them a viable option when liver transplantation, TIPS, or surgical interventions are not feasible [
411–
414]. Although pleurodesis has a reported success rate of 65.4% for managing hepatic hydrothorax, its efficacy is inferior to that of TIPS. Furthermore, complications such as pneumonia, pneumothorax, fistula, and empyema occur in up to 82% of cases, with procedure-related mortality rates reaching 45.5%. Consequently, pleurodesis should only be considered as a limited option when TIPS or surgery is not feasible [
415–
417]. Chest tube insertion requires caution in patients with hepatic hydrothorax due to the risk of severe fluid and protein loss, as well as life-threatening complications including empyema, hemothorax, pneumothorax, and HRS [
418–
420]. In cases of spontaneous bacterial empyema, chest tube insertion should also be avoided [
421].
For patients who are not candidates for liver transplantation or TIPS, therapeutic options remain limited. In such cases, intermittent drainage via a percutaneous pigtail catheter or repeated thoracentesis may be attempted for symptom management. However, these approaches should be carefully considered based on the patient’s individual clinical status, and further studies are required to establish standardized protocols [
422–
425].
Areas for future research
Most patients with hepatic hydrothorax exhibit impaired residual liver function. Although liver transplantation is the definitive treatment, practical application is severely limited by the scarcity of donors. Furthermore, TIPS offers minimal prognostic benefit in patients with poor liver function. While recent studies have suggested indwelling pleural catheter as an alternative for patients who are poor candidates for transplantation or TIPS, this option has not yet been introduced in Korea, and clinical research remains insufficient. Currently, pigtail catheter insertion or repeated thoracentesis are primarily utilized in clinical practice; however, largescale prospective studies are required to evaluate the efficacy and safety of these interventions.
Recommendations
1. The first-line treatment for hepatic hydrothorax is sodium restriction and diuretic therapy. (B1)
2. In patients with refractory hepatic hydrothorax, TIPS can be performed (B2), and liver transplantation should ultimately be considered. (A1)
Abdominal hernia
Abdominal hernias, including umbilical, inguinal, and femoral hernias, are common in patients with cirrhotic ascites, with umbilical hernias observed in up to 20% of patients [
426]. Increased intra-abdominal pressure due to ascites, weakened abdominal musculature, and malnutrition contribute to hernia formation. Hernia development may be prevented by effective ascites control. Use of abdominal binders and manual support of the hernia site during activities that increase intra-abdominal pressure, such as coughing, may be helpful.
Rapid decompression of ascites following LVP, peritoneovenous shunting, or TIPS may precipitate incarceration when bowel or mesentery is present within the hernia sac [
427,
428]. Failure of manual reduction may result in bowel necrosis or perforation, necessitating emergency surgery. Patients should be instructed to seek immediate medical attention if abdominal pain develops.
In patients awaiting liver transplantation, hernia repair should be performed concurrently with or after transplantation [
429]. In non-transplant candidates, surgical decision-making should balance operative risk and benefit [
430–
432]. Emergency surgery is indicated for incarcerated hernias that cannot be manually reduced, even in patients with poor liver function [
433]. Elective hernia repair may be considered to improve quality of life in patients with relatively preserved liver function [
434]. Analysis of 778 cirrhotic patients with ascites revealed a sharp increase in postoperative complications as MELD scores rose: 15% (<10), 20% (10–19), 42% (20–29), and 100% (>30) [
435]. Consistent with these findings, multiple studies found that a MELD (or MELD-Na) score above 10–15 or a Child-Pugh score of 7 or higher was associated with significantly higher mortality after hernia repair [
436–
438].
In patients with preoperative ascites, hernia recurrence rates can reach up to 73% following surgery [
439,
440]. Furthermore, the 30-day postoperative complication rate is significantly higher in patients with ascites compared to those without (19% vs. 4%,
P<0.001), highlighting the critical importance of preoperative ascites control [
435]. Emergency surgery for non-incarcerated hernias in the absence of adequate ascites control is not recommended due to increased risk of mortality and complications. Conversely, a ‘wait-and-see’ approach carries risks such as incarceration, infection, skin necrosis, umbilical hernia rupture with ascites leakage, evisceration, and peritonitis. Therefore, elective surgery is recommended once sufficient ascites control is achieved [
439,
441–
443].
A multidisciplinary approach should be adopted, considering the patient’s symptoms, nutritional status, degree of ascites control, and residual liver function to determine the most appropriate management strategy, including liver transplantation, TIPS, or surgical repair [
439,
444]. Postoperatively, all patients are advised to limit daily sodium intake to 2,000 mg (5 g of salt) and minimize the use of high-sodium intravenous fluids to prevent recurrence.
Areas for future research
Abdominal hernias predominantly occur in patients with refractory ascites and advanced liver dysfunction, limiting therapeutic options other than transplantation. Future research should focus on developing safe and effective treatment strategies for this high-risk population.
Recommendations
1. In patients with cirrhotic ascites, effective control of ascites is essential to prevent the development and progression of abdominal hernias. (B1)
2. Elective hernia repair can be considered in patients with well-controlled ascites and preserved liver function. (B1)
CONSIDERATIONS FOR MEDICATION USE IN PATIENTS WITH CIRRHOSIS
Changes in drug metabolism in cirrhosis and portosystemic shunting
Drugs are excreted through hepatic metabolism, which converts lipophilic drugs into water-soluble metabolites; this process is determined by hepatic blood flow and hepatocyte enzyme activity. In cirrhosis, intrinsic clearance decreases, and hemodynamic changes occur due to portosystemic shunting. In advanced stages, factors such as hypoalbuminemia, portal hypertensive gastropathy, ascites, and reduced renal blood flow affect the absorption, distribution, bioavailability, and elimination of drugs, leading to significant pharmacokinetic and pharmacodynamic alterations [
445,
446]. Clinical efficacy may change even without pharmacokinetic shifts; for example, the natriuretic effect of furosemide is significantly reduced in patients with ascites compared to controls [
447]. When portosystemic shunts are present, naturally or via TIPS, the bypassed first-pass effect increases drug bioavailability, requiring dose reductions for drugs with high hepatic extraction ratios [
448,
449] Additionally, caution is warranted with QT-prolonging agents like quinolones due to the increased risk of arrhythmia in patients with shunts [
448,
450].
Ultimately, delayed drug clearance in cirrhosis increases the risk of toxicity and adverse events due to elevated plasma concentrations and prolonged half-lives. Unlike chronic kidney disease, which offers well-established indicators for dose adjustment such as glomerular filtration rate (GFR), liver disease presents a clinical challenge because no single surrogate marker can definitively guide dosage. Consequently, clinicians must adopt an individualized approach, tailoring treatment based on the patient’s hepatic functional status.
Acetaminophen
Acetaminophen (AAP) is a potential intrinsic hepatotoxin that interferes with hepatocyte metabolism or disrupts cellular integrity; it can also rarely induce idiosyncratic hepatotoxicity [
451,
452]. Hepatotoxicity is uncommon when the daily dose is maintained below the recommended maximum of 4 g [
453]. However, AAP possesses a narrow therapeutic index, meaning that a dose of 7–8 g, merely twice the maximum allowable limit, can lead to hepatocellular necrosis and subsequent liver failure. This risk is further compounded in patients with impaired liver function or chronic alcohol consumption, where the induction of CYP2E1 and glutathione depletion may trigger toxicity even at low doses; consequently, severe liver injury and failure have been reported even when the daily intake of AAP was less than 4 g [
454,
455].
Nevertheless, clinical studies in patients with cirrhosis have shown that short-term administration (within 14 days) of less than 3–4 g per day did not result in significant hepatotoxicity in those with compensated cirrhosis [
456–
458]. Furthermore, long-term administration of approximately 2 g per day was not reported to trigger acute decompensation [
459,
460]. Accordingly, the recommended AAP dosage for patients with liver disease is up to 4 g per day for short-term use, and within 3 g per day for long-term use, while those with cirrhosis or chronic alcohol intake should not exceed 2–3 g per day [
461].
In summary, while appropriate doses of AAP may be administered to patients with liver disease, including those with decompensated cirrhosis, vigilant monitoring for liver injury remains essential, and chronic high-dose use is not recommended in cases of severe hepatic impairment.
Non-steroidal anti-inflammatory drugs (NSAIDs)
According to a 2012 study on the prescription patterns of anti-inflammatory analgesics in Korea, NSAIDs were prescribed more frequently than AAP for patients with cirrhosis [
462]. However, there are clinical concerns about elevated plasma concentrations of NSAIDs related to reduced cytochrome P450-mediated metabolism and decreased serum protein binding in patients with cirrhosis, which may result in not only direct hepatotoxicity but also impaired renal function and reduced sodium excretion, thereby inducing diuretic-refractory ascites and edema [
463–
466]. Furthermore, they have been reported to double the risk of variceal and ulcer bleeding [
467–
469]. Therefore, extreme caution is needed when administering NSAIDs in patients with cirrhosis.
Regarding celecoxib, a selective cyclooxygenase-2 inhibitor, research on its safety in patients with cirrhosis remains insufficient; notably, at the time of FDA approval, it was recommended to reduce the dose by 50% for Child-Pugh B patients and to avoid its use entirely for Child-Pugh C patients. While one clinical trial involving nine cirrhotic patients with ascites reported no significant changes in renal function or diuretic response after five days of celecoxib at 200 mg/day, another pilot study reported a GFR decrease of over 20% in four out of nine patients at the same dosage, suggesting that definitive evidence for its safety is still lacking [
466,
470]. Meta-analyses comparing celecoxib with other NSAIDs in patients with liver disease have reported that while it offered better gastrointestinal protection, its analgesic efficacy was similar, and it significantly increased the risk of cardiovascular adverse events [
471,
472]. Therefore, while celecoxib may offer some advantages in terms of gastrointestinal safety, it should be used with caution during long-term administration in patients with decompensated cirrhosis due to potential cardiovascular and renal risks.
In summary, given the heightened risk of renal impairment, cardiovascular events, and gastrointestinal bleeding, the use of NSAIDs in patients with advanced liver disease must be strictly monitored.
Opioids
Opioids may be utilized for the management of severe pain and do not inherently induce hepatotoxicity; however, since they are primarily metabolized in the liver, patients with impaired hepatic function face a heightened risk of severe adverse effects, including ileus, respiratory depression, and hepatic encephalopathy [
473]. Morphine and oxycodone have been reported to show approximately 2–4-fold increases in half-life and bioavailability in patients with cirrhosis and in liver transplant candidates with impaired hepatic function [
474,
475]. Regarding fentanyl and hydromorphone, although single-dose administrations have shown no distinct changes in plasma concentration or half-life in patients with compensated cirrhosis, data for those with severe hepatic impairment remain insufficient [
453,
476–
478]; furthermore, the absorption and onset of action for long-acting or transdermal formulations are difficult to predict in this population. Therefore, when administering potent opioids for severe pain in patients with impaired hepatic function, clinicians should ideally initiate treatment at the lowest possible dose and adjust the dosage while closely monitoring both the therapeutic response and the emergence of potential side effects.
Tramadol, a relatively weak opioid that exerts analgesic effect by binding to μ-opioid receptors and inhibiting serotonin/ norepinephrine reuptake, can be used with relative safety due to its minimal effect on respiratory depression. However, as its half-life more than doubles in patients with impaired liver function, it is recommended to start at a dose of 50 mg or less every 12 hours for patients with decompensated cirrhosis [
479]. Caution is also required regarding the potential for serotonin syndrome and toxicity when co-administered with selective serotonin reuptake inhibitors, tricyclic antidepressants, or anticonvulsants [
480,
481].
Non-selective beta-blockers (NSBBs) such as carvedilol, propranolol, and nadolol are recommended for the prevention of variceal bleeding, as they can improve portal hypertension by reducing cardiac output and promoting splanchnic vasoconstriction, thereby decreasing portal blood flow [
482]. Accordingly, recent studies suggest that NSBBs may help prevent the development of decompensated complications such as ascites and esophageal variceal bleeding in patients with compensated cirrhosis and portal hypertension [
483–
486]. However, since oral NSBBs are metabolized in the liver, there are concerns regarding hypotension or bradycardia due to increased bioavailability; in patients with decompensated cirrhosis and ascites, they may cause weakened cardiac compensatory function, hypotension, and subsequent renal impairment, necessitating monitoring criteria for systolic blood pressure (>90 mmHg) and heart rate (e.g., 55–60 beats/min for propranolol) [
487,
488].
In patients with cirrhosis and ascites, low-dose propranolol (≤80 mg/day) or carvedilol (≤6.25–12.5 mg/day) was not associated with adverse outcomes and was linked to improved survival in several studies [
120,
121,
123–
127,
489–
491]. In contrast, high-dose administration (propranolol ≥160 mg/day or carvedilol ≥25 mg/day) was reported to worsen survival [
121,
125–
127,
489,
490]. Notably, two prospective studies in patients with cirrhosis and refractory ascites reported that the median survival for the propranolol group was significantly shorter compared to the control group, along with increased risk of paracentesis-induced circulatory dysfunction; in interpreting these results, it should be considered that high doses (e.g., 160 mg/day of propranolol) were used in a significant portion (47% and 70%) of the study population [
487,
492,
493]. Therefore, when administering NSBBs to patients with cirrhosis and ascites, clinicians should initiate treatment at a low dose and adjust the dosage while periodically monitoring for hypotension, circulatory dysfunction, renal impairment, and other potential adverse effects.
Renin-angiotensin-aldosterone system (RAAS) inhibitors, commonly used antihypertensive agents, have theoretically been expected to reduce portal hypertension and prevent liver fibrosis by improving hepatic blood flow in patients with liver disease [
494,
495]. However, these agents failed to suppress renin activity in patients with ascites and instead interfered with diuretic action, leading to hypotension and renal impairment in an earlier randomized controlled trial using captopril; therefore, RAAS inhibitors have been discouraged in patients with ascites [
496,
497].
More recently, a meta-analysis of 22,736 cirrhotic patients with hypertension reported that RAAS inhibitor use was associated with significantly reduced risk of liver-related complications, hepatocellular carcinoma, and mortality, while another meta-analysis of 19 clinical trials also indicated a significant reduction in portal pressure compared to control groups [
495,
498]. However, some studies reported discontinuation due to hypotension or renal impairment among patients with Child–Pugh class B or C [
499–
501]. Another meta-analysis restricted to 11 randomized prospective trials reported no improvement in portal pressure and suggested increased risk of symptomatic hypotension with RAAS inhibitors [
502]. Nevertheless, a retrospective study analyzing hospitalized patients with decompensated cirrhosis reported that those receiving a stable dose of RAAS inhibitors (7%) had more stable renal function on hospital day 28 than those not receiving RAAS inhibitors [
503].
In summary, RAAS inhibitors may confer potential prognostic benefits in patients with cirrhosis. Discontinuation is not necessarily required in patients who are stable on a fixed dose; however, when initiating RAAS inhibitors in decompensated cirrhosis, clinicians should monitor for hypotension and renal deterioration.
Statins
The risk of serious liver-related complications associated with the use of statins, which are primary agents for hyperlipidemia, is low [
504,
505]. Prospective studies have demonstrated that there are no significant differences in drug-induced elevations of liver enzyme levels between statin-treated groups and control groups in patients with compensated liver disease [
506,
507]. Meta-analyses focusing on patients with compensated cirrhosis have also indicated that the incidence of statin-induced muscle injury does not significantly increase [
508]. Although data regarding decompensated cirrhosis remain limited, a retrospective analysis of 1,191 liver transplant candidates reported no complications severe enough to warrant discontinuation of statins; however, a randomized controlled trial involving 158 patients with variceal bleeding reported that rhabdomyolysis occurred in two patients (3%) receiving 20 mg and 40 mg of simvastatin, respectively, suggesting that statins should be administered with careful monitoring for potential adverse events [
509,
510].
Various population-based reports and meta-analyses suggest that statin use in compensated cirrhosis can reduce the risk of decompensation, liver-related complications, development and recurrence of hepatocellular carcinoma, and overall mortality [
511–
519]. These benefits have been attributed to synergistic mechanisms beyond cholesterol lowering, including the inhibition of inflammation and fibrosis [
513]. Nevertheless, the STATLiver study, which randomized 78 patients with compensated or decompensated cirrhosis to receive atorvastatin for six months, found no significant improvement in prognosis despite the absence of severe adverse events, and the LIVERHOPE study, which randomized 237 patients with decompensated cirrhosis to receive a combination of simvastatin and rifaximin, also reported no significant differences in liver-related complications or survival [
520–
521].
Therefore, in patients with decompensated cirrhosis, statins are relatively safe and do not need to be restricted when used for the treatment of dyslipidemia or cardiovascular disease. However, evidence remains insufficient to prescribe statins solely for prognostic improvement in patients with cirrhosis.
Proton pump inhibitors
Concerns have been raised that proton pump inhibitor (PPI) use in patients with cirrhosis may increase liver-related complications by causing small intestinal bacterial overgrowth, bacterial translocation, and dysbiosis [
522–
525]. In a meta-analysis of 26 studies published up to 2023, PPI use in cirrhosis was significantly linked to higher risk of long-term mortality (HR 1.321, 95% CI 1.103–1.581), decompensation (HR 1.646, 95% CI 1.477–1.835), hepatic encephalopathy (HR 1.968, 95% CI 1.372–2.822), SBP (HR 1.751, 95% CI 1.649–1.859), and other infections (HR 1.370, 95% CI 1.148–1.634) [
526]. However, some argue that the risks attributed to PPIs may be overstated due to confounding factors such as patient baseline conditions, dosage, and duration of use, rather than there being a direct causal link between PPIs and hepatic encephalopathy or SBP [
527–
529]. For example, in a study of 76,251 U.S. veterans, PPI use was associated with lower long-term survival and increased risk of infection and decompensation; however, among a subgroup hospitalized for gastrointestinal bleeding, PPI use correlated with better survival (HR 0.88, 95% CI 0.84–0.91) [
530]. Therefore, PPIs should only be used when there is a clear clinical need and indication in patients with cirrhosis. Notably, as the half-life of esomeprazole increases 1–1.5-fold, omeprazole and rabeprazole increase 2–4-fold, and lansoprazole and pantoprazole increase 3–5-fold and 7–9-fold, respectively, in cirrhosis, clinicians should select agents and doses carefully and monitor patients for symptom improvement and adverse effects [
531].
Potassium-competitive acid blockers such as tegoprazan and fexuprazan, which are widely used today, are reported to have lower hepatotoxicity than PPIs; however, data on their safety in cirrhosis remain limited [
532,
533].
In patients with cirrhosis, maintaining glycemic homeostasis is challenging due to impaired gluconeogenesis and reduced hepatic glycogen storage, leading to lower fasting blood glucose levels [
534]. Additionally, insulin clearance is reduced by portosystemic shunting, significantly raising the risk of hypoglycemia [
534]. Furthermore, splenomegaly or blood loss may shorten erythrocyte lifespan and yield falsely low glycated hemoglobin (HbA1c) values; thus, HbA1c should be interpreted cautiously in cirrhosis [
534].
Metformin, a biguanide and a first-line oral agent for diabetes, has been reported to significantly reduce hepatic encephalopathy compared with nonuse in patients with cirrhosis (23.2% vs. 41.5%,
P=0.002) [
535]. However, a Taiwanese nationwide report suggested that high-dose metformin (≥1,000 mg) contributed to decompensating events (15%) and mortality (13%); accordingly, it is recommended that metformin be used at the lowest effective dose [
536]. Insulin secretagogues such as sulfonylureas and meglitinides are hepatically metabolized and may have increased plasma concentrations in cirrhosis, increasing the risk of hypoglycemia; therefore, they are generally discouraged in patients with decompensated cirrhosis [
537,
538]. Although thiazolidinediones are not generally considered directly hepatotoxic (except troglitazone, which has been withdrawn), they may exacerbate fluid retention and induce ascites in cirrhotic patients, and retrospective analyses have further indicated an increased risk of cardiovascular disease, particularly with rosiglitazone [
539,
540].
α-Glucosidase inhibitors can be used relatively safely in patients with compensated cirrhosis due to their minimal systemic absorption and hepatic metabolism; they reduce postprandial hyperglycemia, may help restore the gut microbiota, and have mild laxative effects that can aid in ammonia control [
541,
542]. Dipeptidyl peptidase-4 inhibitors have shown the potential to inhibit sarcopenia in diabetic patients, and linagliptin, which is unaffected by hepatic function, is preferred over vildagliptin [
543]. Nevertheless, evidence supporting the use of these agents in patients with decompensated cirrhosis remains insufficient.
Sodium-glucose co-transporter 2 inhibitors, which inhibit renal reabsorption of sodium and glucose, offer diuretic effects and have been reported to reduce ascites and other liver-related complications; however, as these are metabolized in the liver, plasma concentrations may remain high in Child–Pugh class C patients, necessitating careful observation for adverse events such as hemodynamic instability, renal impairment, and urinary tract infection [
130,
544–
547].
Due to the scarcity of clinical studies on drug administration in patients with decompensated cirrhosis, clinicians are often compelled to indirectly estimate appropriate dosages and associated risks based on pharmacokinetic data and research involving patients with compensated cirrhosis or other liver diseases. Furthermore, in real-world clinical settings, medications are frequently necessary despite their known risks; consequently, drug dosages must be adjusted based on individual patient circumstances while closely observing for potential adverse effects across varying degrees of decompensated cirrhosis. To address these challenges, future prospective comparative studies, retrospective analyses, and systematic reviews are essential to provide more definitive evidence-based guidelines.
Recommendations
1. In patients with cirrhosis, both therapeutic efficacy and adverse events must be closely monitored when administering medications. (A1)
2. When acetaminophen administration is required in patients with decompensated cirrhosis, the dosage should be adjusted to within 2–3 g per day. (B1)
3. When administering non-steroidal anti-inflammatory drugs to patients with decompensated cirrhosis, attention should be paid to potential complications such as ascites, edema, renal impairment, and gastrointestinal bleeding. (B1)
4. When opioids are used for the management of severe pain in patients with decompensated cirrhosis, treatment should be initiated at a low dose while monitoring for potential side effects. (B1)
5. When using beta-blockers or renin-angiotensin-aldosterone system inhibitors in patients with cirrhosis and ascites, clinicians must monitor for adverse events such as circulatory dysfunction and renal impairment. (A1)
6. In patients with decompensated cirrhosis, statins can be utilized for the treatment of cardiovascular diseases. (B1)
7. Proton pump inhibitors should be used according to clear indications in patients with cirrhosis. (A1)
8. When using oral hypoglycemic agents in patients with decompensated cirrhosis, attention should be paid to agent-specific adverse effects, such as hypoglycemia. (B1)
FOOTNOTES
-
Authors’ contributions
List of author contributions is available at the official website of Clinical and Molecular Hepatology (Supplementary Material 8, https://doi.org/10.3350/cmh.2026.0281).
-
Conflicts of Interest
A conflicts of interest statement is available at the official website of Clinical and Molecular Hepatology (Supplementary Material 9, https://doi.org/10.3350/cmh.2026.0281).
SUPPLEMENTARY MATERIAL
Supplementary material is available at Clinical and Molecular Hepatology website (
http://www.e-cmh.org).
Supplementary Material 1.
Key question
In patients with liver cirrhosis undergoing intermittent paracentesis, what is the incidence of procedure-related complications?
cmh-2026-0281-Supplementary-Material-1.pdf
Supplementary Material 2.
Key question
In patients with ascites, is the serum–ascites albumin gradient (SAAG) useful for diagnosing the etiology of ascites and predicting ascites-related complications?
cmh-2026-0281-Supplementary-Material-2.pdf
Supplementary Material 3.
Key question
Does intravenous albumin administration in combination with standard of care reduce overall mortality and significantly decrease the incidence of renal failure in patients with liver cirrhosis, compared to standard of care alone?
cmh-2026-0281-Supplementary-Material-3.pdf
Supplementary Material 4.
Key question
Is Transjugular Intrahepatic Portosystemic Shunt (TIPS) more effective than repeated Large-Volume Paracentesis (LVP) for survival, ascites control, and management of cirrhosis- related complications in patients with refractory ascites?
cmh-2026-0281-Supplementary-Material-4.pdf
Supplementary Material 6.
Key question
Is the urinary neutrophil gelatinase-associated lipocalin (uNGAL) test useful for differentiating between acute tubular necrosis (ATN) and hepatorenal syndrome (HRS) in patients with liver cirrhosis, and for predicting their prognosis?
cmh-2026-0281-Supplementary-Material-6.pdf
Supplementary Material 7.
Key question
Does transjugular intrahepatic portosystemic shunt (TIPS) improve renal function and survival in patients with hepatorenal syndrome?
cmh-2026-0281-Supplementary-Material-7.pdf
Figure 1Algorithm for the differential diagnosis of ascites.
Figure 2Treatment algorithm for acute kidney injury in patients with cirrhosis.
Table 1Grading system (grading of recommendations, assessment, development and evaluation)
Table 1
|
Criteria |
|
|
Quality of evidence |
|
High quality (A) |
Further research is very unlikely to change our confidence in the estimate of effect. |
|
Moderate quality (B) |
Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. |
|
Low quality (C) |
Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertain. |
|
Very low (D) |
Any estimate of effect is very uncertain. |
|
Strength of recommendation |
|
Strong (1) |
Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost. |
|
Weak (2) |
Variability in preference and values, or more uncertainty.
Recommendation is made with less certainty and higher cost or resource consumption. |
Table 2Differential diagnosis of ascites
Table 2
|
Category |
Causes |
|
Hepatic diseases |
Liver cirrhosis
Acute liver failure
Budd–Chiari syndrome
Sinusoidal obstruction syndrome
Portal vein thrombosis |
|
Extrahepatic diseases |
Malignant ascites (peritoneal carcinomatosis, massive liver metastases)
Tuberculous peritonitis
Heart failure
Pancreatitis
Nephrotic syndrome
Bowel perforation
Myxedema due to hypothyroidism |
|
Mixed hepatic and extrahepatic diseases |
Mixed ascites due to liver cirrhosis and other causes |
Table 3Diagnostic tests for ascites
Table 3
|
Category |
Tests |
Clinical purpose |
|
Mandatory |
Cell count and differential
Albumin
Total protein |
Etiologic evaluation, spontaneous bacterial peritonitis diagnosis |
|
Optional |
Gram’s stain
Culture in blood culture bottle |
Infection (identification of causative organisms) |
Cytology
Carcinoembryonic antigen |
Malignant ascites |
Acid-fast bacilli smear and culture
Adenosine deaminase |
Tuberculous peritonitis |
Lactate dehydrogenase
Glucose |
Secondary bacterial peritonitis |
|
Amylase |
Pancreatic ascites |
|
Triglyceride |
Chylous ascites |
|
Bilirubin |
Perforation of bile duct |
|
Urea, creatinine |
Urinary ascites |
|
Serum BNP |
Ascites due to heart failure |
Table 4Treatment of ascites in liver cirrhosis
Table 4
|
Grade 1 |
Grade 2 |
Grade 3 |
|
Sodium restriction |
• |
• |
• |
|
Diuretics |
|
• |
• |
|
Paracentesis |
|
|
• |
|
General management |
Treatment of underlying liver disease
Nutritional therapy and education
Discontinue NSAIDs, ACE inhibitors, or angiotensin receptor blockers |
Table 5Classification and diagnostic criteria of refractory ascites
Table 5
|
Classification |
|
|
Refractory ascites |
Ascites that is diuretic-resistant or diuretic-intractable |
|
Diuretic-resistant ascites |
Ascites that cannot be mobilized or that recurs early despite dietary sodium restriction and diuretic treatment |
|
Diuretic-intractable ascites |
Ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of the development of diuretic-induced complications that preclude the use of an effective diuretic dosage |
|
Detailed diagnostic criteria for refractory ascites
|
|
Adequate diuretic dose and duration |
At least 1 week of maximal diuretic therapy (spironolactone 400 mg/day and furosemide 160 mg/day) with dietary salt intake <5 g/day |
|
Treatment response |
Weight loss <0.8 kg over 4 days and urinary sodium excretion less than sodium intake |
|
Early recurrence |
Recurrence of grade 2–3 ascites within 4 weeks of therapeutic paracentesis |
|
Diuretic-related complications |
Hepatic encephalopathy without other precipitating factors; Acute kidney injury (increase in serum creatinine ≥0.3 mg/dL within 48 h or ≥1.5-fold within 7 days, or urine output ≤0.5 mL/kg/h for ≥6 h); Hyponatremia (serum sodium decrease >10 mmol/L to <125 mmol/L); Hypokalemia (<3 mmol/L) or hyperkalemia (>6 mmol/L) |
Table 6Causative organisms and antimicrobial resistance rates of spontaneous bacterial peritonitis in Korea
Table 6
|
Article |
Period |
Classification |
Gram-negative (%) |
Gram-positive (%) |
Resistance rate (%) |
|
Yim et al. [204] |
2007–2018 |
Mainly community-acquired |
E. coli (34.1)
Klebsiella species (29.3)
Aeromonas species (6.1) |
Streptococcus species (20.7)
Staphylococcus species (3.7)
Enterococcus species (1.2) |
ESBL-producing E. coli (10.7), Klebsiella species (8.3)
Cefotaxime-resistant E. coli (10.7), Klebsiella species (8.3)
Fluoroquinolone-resistant E. coli (46.4), Streptococcus species (11.8)
Piperacillin-resistant E. coli (14.3), Klebsiella species (16.7) |
|
Kim et al. [205] |
2000–2011 |
Community-acquired |
E. coli (67.7)
Klebsiella pneumoniae (36.9)
Aeromonas species (7.7) |
Streptococcus species (12.3)
Streptococcus pneumoniae (10.8)
Staphylococcus aureus (3.1) |
ESBL-producers (1.6)
Third-generation cephalosporins resistance (1.6)
Fluoroquinolones resistance (9.8) |
|
Healthcare-associated |
E. coli (43.1)
Klebsiella pneumoniae (22.8)
Aeromonas species (4.9) |
Streptococcus species (7.3)
Streptococcus pneumoniae (3.3)
Staphylococcus aureus (2.4) |
ESBL-producers (3.4)
Third-generation cephalosporins resistance (6.8)
Fluoroquinolones-resistance (16.2) |
|
Na et al. [206] |
2005–2014 |
Not stated |
E. coli (39.4)
Klebsiella species (17.8)
Pseudomonas aeruginosa (3.5) |
Viridans streptococci (8.1)
Enterococcus species (3.5)
Staphylococcus aureus (2.7) |
ESBL-producing E. coli (18.6), Klebsiella pneumoniae (17.4) |
|
Kim et al. [207] |
2006–2013 |
Community-acquired + Nosocomial |
E. coli (32.4)
Klebsiella species (19.4)
Aeromonas species (5.1) |
Enterococcus species (12.9)
Staphylococcus aureus (12.9)
Streptococcus species (9.0) |
ESBL-producing E. coli (16), Klebsiella pneumoniae (40)
Vancomycin-resistant Enterococcus species (20)
Methicillin-resistant Staphylococcus aureus (60) |
|
Kim et al. [208] |
2013–2018 |
Community-acquired + Nosocomial |
-
|
-
|
ESBL-producing E. coli (25), Klebsiella species (9)
Carbapenem-resistant Acinetobacter baumannii (2)
Methicillin-resistant Staphylococcus aureus (2) |
|
Kim et al. [209], Bae et al. [210] |
1997–2013 |
Community-acquired + Nosocomial |
E. coli (45.7)
Klebsiella species (16.7)
Aeromonas species (5.3) |
Enterobacter species (2.7)
Streptococci other than S. pneumoniae (10.1)
Streptococcus pneumoniae (4.3) |
Third-generation cephalosporins-resistant E. coli (15.2), Enterobacter species (29), Streptococcus pneumoniae (2.2)
Ciprofloxacin-resistant E. coli (39.2), Enterobacter species (19.4)
Levofloxacin resistant Streptococcus pneumoniae (0)
Piperacillin/Tazobactam-resistant E. coli (7.2), Enterobacter species (25.8) |
|
Cheong et al. [211] |
2000–2007 |
Community-acquired + Nosocomial |
E. coli (43.2%)
Klebsiella species (14.0%)
Aeromonas (4.6%) |
Streptococcus species (13.2%)
Enterococcus (4.2%)
Staphylococcus aureus (5.1%) |
Third-generation cephalosporin resistant GNB (13.7)
Quinolone-resistant GNB (19.8)
ESBL-producing GNB (6.0) |
|
Kim et al. [212] |
2000–2011 |
Community-acquired |
E. coli (44.3%) |
|
Fluoroquinolone-resistant E. coli (31.7)
Third-generation cephalosporin-resistance E. coli (7.3)
ESBL-producing E. coli (6.1) |
|
Song et al. [213] |
1998–2003 |
Community-acquired |
E. coli (59.4)
Klebsiella pneumoniae (7.7) |
|
Cefotaxime resistance E. coli (13.6)
ESBL-producing E. coli (13.6)
Ciprofloxacin resistance E. coli (13.6) |
|
Nosocomial |
E. coli (56.3)
Klebsiella pneumoniae (18.8) |
|
Cefotaxime resistance E. coli (77.7)
ESBL-producing E. coli (66.7)
Ciprofloxacin resistance E. coli (44.4) |
Table 7Diagnostic criteria for acute kidney injury in patients with cirrhosis
110
Table 7
|
Definition |
Increase in serum creatinine ≥0.3 mg/dl (26.5 μmol/L) within 48 hours or ≥50% from baseline value known or presumed to have occurred within the prior 7 days and/or urine output ≤0.5 mL/kg for ≥6 hours |
|
Staging |
|
Stage 1 |
Increase in sCr ≥0.3 mg/dL or an increase in sCr ≥1.5-fold to 2-fold from baseline |
|
Stage 2 |
Increase in sCr >2-fold to 3-fold from baseline |
|
Stage 3 |
Increase in sCr >3-fold from baseline or sCr ≥4.0 mg/dL with an acute increase ≥0.3 mg/dL or initiation of renal replacement therapy |
Table 8Diagnostic criteria for hepatorenal syndrome–acute kidney injury (HRS-AKI)
Table 8
|
1) Cirrhosis with ascites |
2) Meeting diagnostic criteria for acute kidney injury:
Increase in serum creatinine ≥0.3 mg/dL (26.5 μmol/L) within 48 hours or ≥50% from baseline value known or presumed to have occurred within the prior 7 days and/or urine output ≤0.5 mL/kg for ≥6 hours |
|
3) No improvement in sCr or urine output after diuretic withdrawal and 1–2 days of adequate volume expansion with albumin (1 g/kg/day, maximum 100 g) or crystalloid solutions |
|
4) Absence of other causes of AKI, including septic shock, acute glomerular injury, urinary tract obstruction, or nephrotoxic injury |
Table 9Clinical utility of urinary NGAL for distinguishing ATN from HRS
Table 9
|
First author |
Country |
Age (years) |
Male (%) |
MELD |
Total |
No. of ATN cases |
Biomarker assay |
AUROC |
Optimal cutoff (ng/mL) |
Optimal cutoff (μg/g creatinine) |
|
Ariza et al. [321] |
Spain |
58 |
78 |
23 |
55 |
12 |
Bead-based immunoassay |
0.95 |
236 |
294 |
|
Gambino et al. [322] |
Italy |
NR |
NR |
NR |
162 |
27 |
CLIA (Abbott) |
0.85 |
220 |
223 |
|
George et al. [323] |
India |
49 |
86 |
29 |
86 |
14 |
ELISA (Elabscience) |
0.97 |
215 |
179 |
|
Belcher et al. [320] |
USA |
55 |
69 |
26 |
110 |
39 |
ELISA (BioPorto) |
0.78 |
365 |
158 |
|
Huelin et al. [324] |
Spain |
62 |
72 |
22 |
320 |
39 |
TIA (BioPorto) |
0.80 |
NR |
220 |
|
Allegretti et al. [325] |
USA |
58 |
69 |
23 |
161 |
49 |
TIA (BioPorto) |
0.76 |
NR |
244 |
|
Treeprasertsuk et al. [326] |
Thailand |
57 |
62 |
15 |
35 |
9 |
CLIA (Abbott) |
0.91 |
137 |
NR |
|
Qasem et al. [327] |
Egypt |
53 |
64 |
19 |
68 |
22 |
ELISA (BioVandor) |
0.90 |
NR |
286 |
|
Hamdy et al. [328] |
Egypt |
54 |
59 |
20 |
70 |
14 |
ELISA (BioVandor) |
0.82 |
NR |
143 |
|
Fagundes et al. [329] |
Spain |
60 |
63 |
18 |
84 |
33 (HRS) 11 (ATN) |
ELISA (BioPorto) |
NR |
180 |
194 (HRS) |
|
Udgirkar et al. [330] |
India |
47 |
71 |
20 |
94 |
33 (HRS) 10 (ATN) |
CMIA (Abbott) |
0.95 |
650 (HRS) |
NR |
|
Altran et al. [331] |
Brazil |
59 |
72 |
19 |
53 |
23 |
ELISA |
0.65 |
336 |
NR |
|
Ma et al. [332] |
Spain |
62*
|
80 |
23 |
202 |
30 (HRS) 41 (ATN) |
TIA (BioPorto) |
0.78 |
NR |
307 (HRS) |
Table 10Criteria for terlipressin dose adjustment and discontinuation according to treatment response and adverse events in patients with hepatorenal syndrome
Table 10
|
Dose adjustment |
|
|
|
Discontinuation |
Complete response Total treatment duration of 14 days Lack of response after 48–72 hours at the maximum dose Occurrence of serious adverse events (peripheral ischemia, myocardial ischemia, arrhythmia, pulmonary edema) Initiation of renal replacement therapy or liver transplantation
|
Table 11Definitions of treatment response to terlipressin therapy in patients with hepatorenal syndrome
Table 11
|
Non-response |
No improvement in AKI stage |
|
Partial response |
Improvement in AKI stage with sCr remaining ≥0.3 mg/dL above baseline |
|
Complete response |
Improvement in AKI stage with sCr returning to within 0.3 mg/dL of baseline |
Abbreviations
Acute Dialysis Quality Initiative
branched-chain amino acids
culture-negative neutrocytic ascites
extended-spectrum beta-lactamase
food and drug administration
fractional excretion of sodium
fractional excretion of urea
glomerular filtration rate
Grading of Recommendations, Assessment, Development and Evaluation
International Club of Ascites
Korean Association for the Study of the Liver
large volume paracentesis
multidrug-resistant organisms
Model for End-stage Liver Disease
methicillin-resistant Staphylococcus aureus
nonsteroidal anti-inflammatory drug
neutrophil gelatinase–associated lipocalin
non-selective beta-blockers
osmotic demyelination syndrome
paracentesis-induced circulatory dysfunction
polymorphonuclear leukocyte
Renin-angiotensin-aldosterone system
renal replacement therapy
serum–ascites albumin gradient
spontaneous bacterial peritonitis
serum–pleural fluid albumin gradient
transjugular intrahepatic portosystemic shunt
vancomycin-resistant Enterococcus
REFERENCES
- 1. Runyon BA, Montano AA, Akriviadis EA, Antillon MR, Irving MA, McHutchison JG, et al. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites. Ann Intern Med 1992;117:215-220.
- 2. Shaikh MA, Khan J, Almani S, Dur-e-Yakta , Shaikh D. Frequency of causes of ascites in patients admitted at medical unit of a tertiary medical care facility. J Ayub Med Coll Abbottabad 2010;22:88-92.
- 3. Goldberg BB, Goodman GA, Clearfield HR. Evaluation of ascites by ultrasound. Radiology 1970;96:15-22.
- 4. Runyon BA. Care of patients with ascites. N Engl J Med 1994;330:337-342.
- 5. Borzio M, Salerno F, Piantoni L, Cazzaniga M, Angeli P, Bissoli F, et al. Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study. Dig Liver Dis 2001;33:41-48.
- 6. Biggins SW, Angeli P, Garcia-Tsao G, Ginès P, Ling SC, Nadim MK, et al. Diagnosis, evaluation, and management of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome: 2021 practice guidance by the American Association for the Study of Liver Diseases. Hepatology 2021;74:1014-1048.
- 7. Beran A, Mohamed MFH, Vargas A, Aboursheid T, Aziz M, Hernaez R, et al. Early diagnostic paracentesis improves outcomes of hospitalized patients with cirrhosis and ascites: a systematic review and meta-analysis. Am J Gastroenterol 2024;119:2259-2266.
- 8. Sakai H, Sheer TA, Mendler MH, Runyon BA. Choosing the location for non-image guided abdominal paracentesis. Liver Int 2005;25:984-986.
- 9. Webster ST, Brown KL, Lucey MR, Nostrant TT. Hemorrhagic complications of large volume abdominal paracentesis. Am J Gastroenterol 1996;91:366-368.
- 10. Runyon BA. Paracentesis of ascitic fluid. A safe procedure. Arch Intern Med 1986;146:2259-2261.
- 11. Pache I, Bilodeau M. Severe haemorrhage following abdominal paracentesis for ascites in patients with liver disease. Aliment Pharmacol Ther 2005;21:525-529.
- 12. Liebowitz HR. Hazards of abdominal paracentesis in the cirrhotic patient. N Y State J Med 1962;62:2223-2229.
- 13. Thomson A, Cain P, Kerlin P, Strong R. Serious hemorrhage complicating diagnostic abdominal paracentesis. J Clin Gastroenterol 1998;26:306-308.
- 14. Arnold C, Haag K, Blum HE, Rössle M. Acute hemoperitoneum after large-volume paracentesis. Gastroenterology 1997;113:978-982.
- 15. McGibbon A, Chen GI, Peltekian KM, van Zanten SV. An evidence-based manual for abdominal paracentesis. Dig Dis Sci 2007;52:3307-3315.
- 16. Nazeer SR, Dewbre H, Miller AH. Ultrasound-assisted paracentesis performed by emergency physicians vs the traditional technique: a prospective, randomized study. Am J Emerg Med 2005;23:363-367.
- 17. Cho J, Jensen TP, Reierson K, Mathews BK, Bhagra A, Franco-Sadud R, et al. Recommendations on the use of ultrasound guidance for adult abdominal paracentesis: a position statement of the Society of Hospital Medicine. J Hosp Med 2019;14:E7-E15.
- 18. Grabau CM, Crago SF, Hoff LK, Simon JA, Melton CA, Ott BJ, et al. Performance standards for therapeutic abdominal paracentesis. Hepatology 2004;40:484-488.
- 19. Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. J Thromb Haemost 2006;4:721-723.
- 20. Caldwell SH, Hoffman M, Lisman T, Macik BG, Northup PG, Reddy KR, et al. Coagulation disorders and hemostasis in liver disease: pathophysiology and critical assessment of current management. Hepatology 2006;44:1039-1046.
- 21. Raco J, Bufalini J, Dreer J, Shah V, King L, Wang L, et al. Safety of abdominal paracentesis in hospitalised patients receiving uninterrupted therapeutic or prophylactic anticoagulants. Intern Med J 2025;55:77-83.
- 22. Patel IJ, Rahim S, Davidson JC, Hanks SE, Tam AL, Walker TG, et al. Society of Interventional Radiology consensus guidelines for the periprocedural management of thrombotic and bleeding risk in patients undergoing percutaneous image-guided interventions-Part II: recommendations: endorsed by the Canadian Association for Interventional Radiology and the Cardiovascular and Interventional Radiological Society of Europe. J Vasc Interv Radiol 2019;30:1168-1184e1.
- 23. Kuperman E, Hobbs RA. Major bleeding after paracentesis associated with apixaban use: two case reports. Hosp Pharm 2023;58:34-37.
- 24. Hernaez R, Hamilton JP. Unexplained ascites. Clin Liver Dis (Hoboken) 2016;7:53-56.
- 25. Runyon BA. Cardiac ascites: a characterization. J Clin Gastroenterol 1988;10:410-412.
- 26. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, et al, eds. Harrison’s principles of internal medicine. 22nd ed. New York: McGraw Hill; 2025.
- 27. Jeffries MA, Stern MA, Gunaratnam NT, Fontana RJ. Unsuspected infection is infrequent in asymptomatic outpatients with refractory ascites undergoing therapeutic paracentesis. Am J Gastroenterol 1999;94:2972-2976.
- 28. Evans LT, Kim WR, Poterucha JJ, Kamath PS. Spontaneous bacterial peritonitis in asymptomatic outpatients with cirrhotic ascites. Hepatology 2003;37:897-901.
- 29. Runyon BA, Umland ET, Merlin T. Inoculation of blood culture bottles with ascitic fluid. Improved detection of spontaneous bacterial peritonitis. Arch Intern Med 1987;147:73-75.
- 30. Runyon BA, Hoefs JC, Morgan TR. Ascitic fluid analysis in malignancy-related ascites. Hepatology 1988;8:1104-1109.
- 31. Ahadi M, Tehranian S, Memar B, Vossoughinia H, Salari M, Eskandari E, et al. Diagnostic value of carcinoembryonic antigen in malignancy-related ascites: systematic review and meta-analysis. Acta Gastroenterol Belg 2014;77:418-424.
- 32. Akriviadis EA, Runyon BA. Utility of an algorithm in differentiating spontaneous from secondary bacterial peritonitis. Gastroenterology 1990;98:127-133.
- 33. Zhuang TZ, Akhnoukh SB, Morris GD, Krakow DA. Urinary ascites: An imitator of portal hypertension-related ascites. Cureus 2022;14:e29581.
- 34. Matsuura H, Soda D, Kishida M. Gastrointestinal: Urinary ascites: the great mimic. J Gastroenterol Hepatol 2023;38:2051.
- 35. Singh V, De A, Mehtani R, Angeli P, Maiwall R, Satapathy S, et al. Asia-Pacific association for study of liver guidelines on management of ascites in liver disease. Hepatol Int 2023;17:792-826.
- 36. Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A, et al. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on-chronic liver failure. Hepatology 2011;53:774-780.
- 37. Hwangbo Y, Jung JH, Shim J, Kim BH, Jung SH, Lee CK, et al. Etiologic and laboratory analyses of ascites in patients who underwent diagnostic paracentesis. Korean J Hepatol 2007;13:185-195.
- 38. Runyon BA. AASLD Practice Guidelines Committee. Management of adult patients with ascites due to cirrhosis: an update. Hepatology 2009;49:2087-2107.
- 39. Veldt BJ, Lainé F, Guillygomarc’h A, Lauvin L, Boudjema K, Messner M, et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol 2002;36:93-98.
- 40. Moon W, Choi MS, Moon YM, Paik SW, Lee JH, Koh KC, et al. Efficacy and safety of adefovir dipivoxil in patients with decompensated liver cirrhosis with Lamivudine resistance compared to patients with compensated liver disease. Korean J Hepatol 2005;11:125-134.
- 41. Shim JH, Lee HC, Kim KM, Lim YS, Chung YH, Lee YS, et al. Efficacy of entecavir in treatment-naive patients with hepatitis B virus-related decompensated cirrhosis. J Hepatol 2010;52:176-182.
- 42. Yao FY, Bass NM. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection. J Hepatol 2000;33:301-307.
- 43. Manolakopoulos S, Triantos C, Theodoropoulos J, Vlachogiannakos J, Kougioumtzan A, Papatheodoridis G, et al. Antiviral therapy reduces portal pressure in patients with cirrhosis due to HBeAg-negative chronic hepatitis B and significant portal hypertension. J Hepatol 2009;51:468-474.
- 44. Curry MP, O’Leary JG, Bzowej N, Muir AJ, Korenblat KM, Fenkel JM, et al. Sofosbuvir and Velpatasvir for HCV in patients with decompensated cirrhosis. N Engl J Med 2015;373:2618-2628.
- 45. Kim TY, Kim MY, Sohn JH, Kim SM, Ryu JA, Lim S, et al. Sarcopenia as a useful predictor for long-term mortality in cirrhotic patients with ascites. J Korean Med Sci 2014;29:1253-1259.
- 46. Sam J, Nguyen GC. Protein-calorie malnutrition as a prognostic indicator of mortality among patients hospitalized with cirrhosis and portal hypertension. Liver Int 2009;29:1396-1402.
- 47. Alberino F, Gatta A, Amodio P, Merkel C, Di Pascoli L, Boffo G, et al. Nutrition and survival in patients with liver cirrhosis. Nutrition 2001;17:445-450.
- 48. DiMartini A, Cruz RJ, Dew MA, Myaskovsky L, Goodpaster B, Fox K, et al. Muscle mass predicts outcomes following liver transplantation. Liver Transpl 2013;19:1172-1180.
- 49. Englesbe MJ, Patel SP, He K, Lynch RJ, Schaubel DE, Harbaugh C, et al. Sarcopenia and mortality after liver transplantation. J Am Coll Surg 2010;211:271-278.
- 50. Kalafateli M, Mantzoukis K, Choi Yau Y, Mohammad AO, Arora S, Rodrigues S, et al. Malnutrition and sarcopenia predict post-liver transplantation outcomes independently of the Model for End-stage Liver Disease score. J Cachexia Sarcopenia Muscle 2017;8:113-121.
- 51. Bischoff SC, Bernal W, Dasarathy S, Merli M, Plank LD, Schütz T, et al. ESPEN practical guideline: Clinical nutrition in liver disease. Clin Nutr 2020;39:3533-3562.
- 52. Tsien CD, McCullough AJ, Dasarathy S. Late evening snack: exploiting a period of anabolic opportunity in cirrhosis. J Gastroenterol Hepatol 2012;27:430-441.
- 53. Chen CJ, Wang LC, Kuo HT, Fang YC, Lee HF. Significant effects of late evening snack on liver functions in patients with liver cirrhosis: A meta-analysis of randomized controlled trials. J Gastroenterol Hepatol 2019;34:1143-1152.
- 54. Plank LD, Gane EJ, Peng S, Muthu C, Mathur S, Gillanders L, et al. Nocturnal nutritional supplementation improves total body protein status of patients with liver cirrhosis: a randomized 12-month trial. Hepatology 2008;48:557-566.
- 55. Marchesini G, Dioguardi FS, Bianchi GP, Zoli M, Bellati G, Roffi L, et al. Long-term oral branched-chain amino acid treatment in chronic hepatic encephalopathy. A randomized double-blind casein-controlled trial. The Italian Multicenter Study Group. J Hepatol 1990;11:92-101.
- 56. Fukui H, Saito H, Ueno Y, Uto H, Obara K, Sakaida I, et al. Evidence-based clinical practice guidelines for liver cirrhosis 2015. J Gastroenterol 2016;51:629-650.
- 57. Yatsuhashi H, Ohnishi Y, Nakayama S, Iwase H, Nakamura T, Imawari M, et al. Anti-hypoalbuminemic effect of branched-chain amino acid granules in patients with liver cirrhosis is independent of dietary energy and protein intake. Hepatol Res 2011;41:1027-1035.
- 58. Kawamura E, Habu D, Morikawa H, Enomoto M, Kawabe J, Tamori A, et al. A randomized pilot trial of oral branched-chain amino acids in early cirrhosis: validation using prognostic markers for pre-liver transplant status. Liver Transpl 2009;15:790-797.
- 59. Kitajima Y, Takahashi H, Akiyama T, Murayama K, Iwane S, Kuwashiro T, et al. Supplementation with branched-chain amino acids ameliorates hypoalbuminemia, prevents sarcopenia, and reduces fat accumulation in the skeletal muscles of patients with liver cirrhosis. J Gastroenterol 2018;53:427-437.
- 60. Ruiz-Margáin A, Macías-Rodríguez RU, Ríos-Torres SL, Román-Calleja BM, Méndez-Guerrero O, Rodríguez-Córdova P, et al. Effect of a high-protein, high-fiber diet plus supplementation with branched-chain amino acids on the nutritional status of patients with cirrhosis. Rev Gastroenterol Mex (Engl Ed) 2018;83:9-15.
- 61. Kikuchi Y, Hiroshima Y, Matsuo K, Kawaguchi D, Murakami T, Yabushita Y, et al. A randomized clinical trial of preoperative administration of branched-chain amino acids to prevent postoperative ascites in patients with liver resection for hepatocellular carcinoma. Ann Surg Oncol 2016;23:3727-3735.
- 62. Park JG, Tak WY, Park SY, Kweon YO, Jang SY, Lee YR, et al. Effects of branched-chain amino acids (BCAAs) on the progression of advanced liver disease: A Korean nationwide, multicenter, retrospective, observational, cohort study. Medicine (Baltimore) 2017;96:e6580.
- 63. Takaguchi K, Moriwaki H, Doyama H, Iida M, Yagura M, Shimada N, et al. Effects of branched-chain amino acid granules on serum albumin level and prognosis are dependent on treatment adherence in patients with liver cirrhosis. Hepatol Res 2013;43:459-466.
- 64. Aldiabat M, Aljabiri Y, Aleyadeh W, Madi MY, Syn WK, Qureshi K, et al. Branched-Chain Amino Acid supplementation and clinical outcomes in liver cirrhosis: A propensity score-matched multicenter retrospective cohort study. Dig Dis Sci 2026;71:232-247.
- 65. Konstantis G, Pourzitaki C, Chourdakis M, Kitsikidou E, Germanidis G. Efficacy of branched chain amino acids supplementation in liver cirrhosis: a systematic review and meta-analysis. Clin Nutr 2022;41:1171-1190.
- 66. van Dijk AM, Bruins Slot AS, Portincasa P, Siegerink SN, Chargi N, Verstraete CJR, et al. Systematic review with meta-analysis: Branched-chain amino acid supplementation in liver disease. Eur J Clin Invest 2023;53:e13909.
- 67. Kalal C, Benjamin J, Shasthry V, Kumar G, Sharma MK, Joshi YK, et al. Effect of long-term aggressive nutrition therapy on survival in patients with alcohol-related cirrhosis: A randomized controlled trial. Indian J Gastroenterol 2022;41:52-62.
- 68. Meena BL, Taneja S, Tandon P, Sahni N, Soundararajan R, Gorsi U, et al. Home-based intensive nutrition therapy improves frailty and sarcopenia in patients with decompensated cirrhosis: A randomized clinical trial. J Gastroenterol Hepatol 2023;38:210-218.
- 69. Chapman B, Wong D, Sinclair M, Hey P, Terbah R, Gow P, et al. Reversing malnutrition and low muscle strength with targeted enteral feeding in patients awaiting liver transplant: A randomized controlled trial. Hepatology 2024;80:1134-1146.
- 70. Grüngreiff K, Reinhold D, Wedemeyer H. The role of zinc in liver cirrhosis. Ann Hepatol 2016;15:7-16.
- 71. Fialla AD, Israelsen M, Hamberg O, Krag A, Gluud LL. Nutritional therapy in cirrhosis or alcoholic hepatitis: a systematic review and meta-analysis. Liver Int 2015;35:2072-2078.
- 72. Iwasa M, Iwata K, Hara N, Hattori A, Ishidome M, Sekoguchi-Fujikawa N, et al. Nutrition therapy using a multidisciplinary team improves survival rates in patients with liver cirrhosis. Nutrition 2013;29:1418-1421.
- 73. Ahuja H, Sharma BC, Sachdeva S, Mahajan B, Sharma A, Bara S, et al. A double blind randomized controlled trial to assess efficacy of nutritional therapy for prevention of recurrence of hepatic encephalopathy in patients with cirrhosis. J Gastroenterol Hepatol 2023;38:433-440.
- 74. Yu B, Wang J. The efficacy of parenteral nutrition (PN) and enteral nutrition (EN) supports in cirrhosis: a systematic review and network meta-analysis. Medicine (Baltimore) 2022;101:e28618.
- 75. Romeo M, Dallio M, Cipullo M, Coppola A, Mazzarella C, Mammone S, et al. Nutritional and psychological support as a multidisciplinary coordinated approach in the management of chronic liver disease: a scoping review. Nutr Rev 2025;83:1327-1343.
- 76. Wong F. Management of ascites in cirrhosis. J Gastroenterol Hepatol 2012;27:11-20.
- 77. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006;55:Suppl 6. vi1-vi12.
- 78. Reynolds TB. Ascites. Clin Liver Dis 2000;4:151-168. vii.
- 79. Santos J, Planas R, Pardo A, Durández R, Cabré E, Morillas RM, et al. Spironolactone alone or in combination with furosemide in the treatment of moderate ascites in nonazotemic cirrhosis. A randomized comparative study of efficacy and safety. J Hepatol 2003;39:187-192.
- 80. Angeli P, Dalla Pria M, De Bei E, Albino G, Caregaro L, Merkel C, et al. Randomized clinical study of the efficacy of amiloride and potassium canrenoate in nonazotemic cirrhotic patients with ascites. Hepatology 1994;19:72-79.
- 81. Gentilini P, Laffi G, La Villa G, Carloni V, Foschi M, Romanelli RG, et al. Torasemide in the treatment of patients with cirrhosis and ascites. Cardiovasc Drugs Ther 1993;7:Suppl 1. 81-85.
- 82. Bernardi M. Optimum use of diuretics in managing ascites in patients with cirrhosis. Gut 2010;59:10-11.
- 83. Angeli P, Fasolato S, Mazza E, Okolicsanyi L, Maresio G, Velo E, et al. Combined versus sequential diuretic treatment of ascites in non-azotaemic patients with cirrhosis: results of an open randomised clinical trial. Gut 2010;59:98-104.
- 84. Pockros PJ, Reynolds TB. Rapid diuresis in patients with ascites from chronic liver disease: the importance of peripheral edema. Gastroenterology 1986;90:1827-1833.
- 85. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:258-266.
- 86. Dougher CE, Rifkin DE, Anderson CA, Smits G, Persky MS, Block GA, et al. Spot urine sodium measurements do not accurately estimate dietary sodium intake in chronic kidney disease. Am J Clin Nutr 2016;104:298-305.
- 87. Park JE, Lee CH, Kim BS, Shin IH. Diagnostic usefulness of the random urine Na/K ratio in cirrhotic patients with ascites: a pilot study. Korean J Hepatol 2010;16:66-74.
- 88. Morando F, Rosi S, Gola E, Nardi M, Piano S, Fasolato S, et al. Adherence to a moderate sodium restriction diet in out patients with cirrhosis and ascites: a real-life cross-sectional study. Liver Int 2015;35:1508-1515.
- 89. Ghabril M, Jackson M, Gotur R, Weber R, Orman E, Vuppalanchi R, et al. Most individuals with advanced cirrhosis have sleep disturbances, which are associated with poor quality of life. Clin Gastroenterol Hepatol 2017;15:1271-1278e6.
- 90. Sawada Y, Shiraki M, Iwasa M, Hiraoka A, Nakanishi H, Karino Y, et al. The effects of diuretic use and the presence of ascites on muscle cramps in patients with cirrhosis: a nationwide study. J Gastroenterol 2020;55:868-876.
- 91. Angeli P, Albino G, Carraro P, Dalla Pria M, Merkel C, Caregaro L, et al. Cirrhosis and muscle cramps: evidence of a causal relationship. Hepatology 1996;23:264-273.
- 92. Elfert AA, Abo Ali L, Soliman S, Zakaria S, Shehab El-Din I, Elkhalawany W, et al. Randomized placebo-controlled study of baclofen in the treatment of muscle cramps in patients with liver cirrhosis. Eur J Gastroenterol Hepatol 2016;28:1280-1284.
- 93. Abd-Elsalam S, Ebrahim S, Soliman S, Alkhalawany W, Elfert A, Hawash N, et al. Orphenadrine in treatment of muscle cramps in cirrhotic patients: a randomized study. Eur J Gastroenterol Hepatol 2020;32:1042-1045.
- 94. Abd-Elsalam S, Arafa M, Elkadeem M, Elfert A, Soliman S, Elkhalawany W, et al. Randomized-controlled trial of methocarbamol as a novel treatment for muscle cramps in cirrhotic patients. Eur J Gastroenterol Hepatol 2019;31:499-502.
- 95. Ahn S, Hong YH, Lee DH, Joo SK, Jung YJ, Sohn SY, et al. Efficacy and safety of pregabalin for muscle cramps in liver cirrhosis: a double-blind randomized controlled trial. J Korean Med Sci 2022;37:e56.
- 96. Lee JS. Albumin for end-stage liver disease. Korean J Intern Med 2012;27:13-19.
- 97. Gentilini P, Casini-Raggi V, Di Fiore G, Romanelli RG, Buzzelli G, Pinzani M, et al. Albumin improves the response to diuretics in patients with cirrhosis and ascites: results of a randomized, controlled trial. J Hepatol 1999;30:639-645.
- 98. Shrestha DB, Budhathoki P, Sedhai YR, Baniya R, Awal S, Yadav J, et al. Safety and efficacy of human serum albumin treatment in patients with cirrhotic ascites undergoing paracentesis: A systematic review and meta-analysis. Ann Hepatol 2021;26:100547.
- 99. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403-409.
- 100. Fernández J, Monteagudo J, Bargallo X, Jiménez W, Bosch J, Arroyo V, et al. A randomized unblinded pilot study comparing albumin versus hydroxyethyl starch in spontaneous bacterial peritonitis. Hepatology 2005;42:627-634.
- 101. Italian Association for the Study of the Liver (AISF), Italian Society of Transfusion Medicine and Immunohaematology (SIMTI). AISF-SIMTI position paper: The appropriate use of albumin in patients with liver cirrhosis. Dig Liver Dis 2016;48:4-15.
- 102. Caraceni P, Riggio O, Angeli P, Alessandria C, Neri S, Foschi FG, et al. Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial. Lancet 2018;391:2417-2429.
- 103. Solà E, Solé C, Simón-Talero M, Martín-Llahí M, Castellote J, Garcia-Martínez R, et al. Midodrine and albumin for prevention of complications in patients with cirrhosis awaiting liver transplantation. A randomized placebo-controlled trial. J Hepatol 2018;69:1250-1259.
- 104. Ginés P, Arroyo V, Quintero E, Planas R, Bory F, Cabrera J, et al. Comparison of paracentesis and diuretics in the treatment of cirrhotics with tense ascites. Results of a randomized study. Gastroenterology 1987;93:234-241.
- 105. Pozzi M, Osculati G, Boari G, Serboli P, Colombo P, Lambrughi C, et al. Time course of circulatory and humoral effects of rapid total paracentesis in cirrhotic patients with tense, refractory ascites. Gastroenterology 1994;106:709-719.
- 106. Ruiz-del-Arbol L, Monescillo A, Jimenéz W, Garcia-Plaza A, Arroyo V, Rodés J, et al. Paracentesis-induced circulatory dysfunction: mechanism and effect on hepatic hemodynamics in cirrhosis. Gastroenterology 1997;113:579-586.
- 107. Titó L, Ginès P, Arroyo V, Planas R, Panés J, Rimola A, et al. Total paracentesis associated with intravenous albumin management of patients with cirrhosis and ascites. Gastroenterology 1990;98:146-151.
- 108. Tan HK, James PD, Wong F. Albumin may prevent the morbidity of paracentesis-induced circulatory dysfunction in cirrhosis and refractory ascites: a pilot study. Dig Dis Sci 2016;61:3084-3092.
- 109. Arroyo V, Ginès P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164-176.
- 110. Nadim MK, Kellum JA, Forni L, Francoz C, Asrani SK, Ostermann M, et al. Acute kidney injury in patients with cirrhosis: Acute Disease Quality Initiative (ADQI) and International Club of Ascites (ICA) joint multidisciplinary consensus meeting. J Hepatol 2024;81:163-183.
- 111. Wong F. Management of refractory ascites. Clin Mol Hepatol 2023;29:16-32.
- 112. Angeli P, Garcia-Tsao G, Nadim MK, Parikh CR. News in pathophysiology, definition and classification of hepatorenal syndrome: A step beyond the International Club of Ascites (ICA) consensus document. J Hepatol 2019;71:811-822.
- 113. Choi CH, Ahn SH, Kim DY, Lee SK, Park JY, Chon CY, et al. Long-term clinical outcome of large volume paracentesis with intravenous albumin in patients with spontaneous bacterial peritonitis: a randomized prospective study. J Gastroenterol Hepatol 2005;20:1215-1222.
- 114. Shim E, Ryu HJ, Hwang J, Kim SY, Chung EJ. Dietary sodium intake in young Korean adults and its relationship with eating frequency and taste preference. Nutr Res Pract 2013;7:192-198.
- 115. Singh V, Singh A, Singh B, Vijayvergiya R, Sharma N, Ghai A, et al. Midodrine and clonidine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. Am J Gastroenterol 2013;108:560-567.
- 116. Singh V, Dhungana SP, Singh B, Vijayverghia R, Nain CK, Sharma N, et al. Midodrine in patients with cirrhosis and refractory or recurrent ascites: a randomized pilot study. J Hepatol 2012;56:348-354.
- 117. Yang YY, Lin HC, Lee WP, Chu CJ, Lin MW, Lee FY, et al. Association of the G-protein and α2-adrenergic receptor gene and plasma norepinephrine level with clonidine improvement of the effects of diuretics in patients with cirrhosis with refractory ascites: a randomised clinical trial. Gut 2010;59:1545-1553.
- 118. Kurt M. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2011;53:1411-1412.
- 119. Téllez L, Ibáñez-Samaniego L, Pérez Del Villar C, Yotti R, Martínez J, Carrión L, et al. Non-selective beta-blockers impair global circulatory homeostasis and renal function in cirrhotic patients with refractory ascites. J Hepatol 2020;73:1404-1414.
- 120. Bossen L, Krag A, Vilstrup H, Watson H, Jepsen P. Nonselective β-blockers do not affect mortality in cirrhosis patients with ascites: Post Hoc analysis of three randomized controlled trials with 1198 patients. Hepatology 2016;63:1968-1976.
- 121. Bhutta AQ, Garcia-Tsao G, Reddy KR, Tandon P, Wong F, O’Leary JG, et al. Beta-blockers in hospitalised patients with cirrhosis and ascites: mortality and factors determining discontinuation and reinitiation. Aliment Pharmacol Ther 2018;47:78-85.
- 122. Téllez L, Albillos A. Non-selective beta-blockers in patients with ascites: The complex interplay among the liver, kidney and heart. Liver Int 2022;42:749-761.
- 123. Aday AW, Mayo MJ, Elliott A, Rockey DC. The beneficial effect of beta-blockers in patients with cirrhosis, portal hypertension and ascites. Am J Med Sci 2016;351:169-176.
- 124. Onali S, Kalafateli M, Majumdar A, Westbrook R, O’Beirne J, Leandro G, et al. Non-selective beta-blockers are not associated with increased mortality in cirrhotic patients with ascites. Liver Int 2017;37:1334-1344.
- 125. Mookerjee RP, Pavesi M, Thomsen KL, Mehta G, Macnaughtan J, Bendtsen F, et al. Treatment with non-selective beta blockers is associated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol 2016;64:574-582.
- 126. Leithead JA, Rajoriya N, Tehami N, Hodson J, Gunson BK, Tripathi D, et al. Non-selective β-blockers are associated with improved survival in patients with ascites listed for liver transplantation. Gut 2015;64:1111-1119.
- 127. Bang UC, Benfield T, Hyldstrup L, Jensen JE, Bendtsen F. Effect of propranolol on survival in patients with decompensated cirrhosis: a nationwide study based Danish patient registers. Liver Int 2016;36:1304-1312.
- 128. Njei B, McCarty TR, Garcia-Tsao G. Beta-blockers in patients with cirrhosis and ascites: type of beta-blocker matters. Gut 2016;65:1393-1394.
- 129. Bellos I, Kontzoglou K, Psyrri A, Pergialiotis V. Tolvaptan response improves overall survival in patients with refractory ascites: a meta-analysis. Dig Dis 2020;38:320-328.
- 130. Bakosh MF, Ghazy RM, Ellakany WI, Kamal A. Empagliflozin as a novel therapy for cirrhotic refractory ascites: a randomized controlled study. Egypt Liver Journal 2024;14:76.
- 131. Hu K, Goel A, Tarlow B, Cheng X, Kim S, Kim WR, et al. Empagliflozin in diuretic-refractory ascites (DRAin-Em): results of a single-center feasibility study. J Gen Intern Med 2025;40:1680-1682.
- 132. Di Pascoli M, Fasolato S, Piano S, Bolognesi M, Angeli P. Long-term administration of human albumin improves survival in patients with cirrhosis and refractory ascites. Liver Int 2019;39:98-105.
- 133. Pompili E, Zaccherini G, Piano S, Toniutto P, Lombardo A, Gioia S, et al. Real-world experience with long-term albumin in patients with cirrhosis and ascites. JHEP Rep 2024;6:101221.
- 134. Bakhtiar M, Forde KA, Nadolski GJ, Soulen MC, Weinberg EM. Radiologically placed peritoneovenous shunt is an acceptable treatment alternative for refractory ascites due to end-stage liver disease. J Vasc Interv Radiol 2021;32:1606-1614.
- 135. Bucsics T, Hoffman S, Grünberger J, Schoder M, Matzek W, Stadlmann A, et al. ePTFE-TIPS vs repetitive LVP plus albumin for the treatment of refractory ascites in patients with cirrhosis. Liver Int 2018;38:1036-1044.
- 136. Bañares R, Albillos A, Nakum M, Gea S, Varghese A, Green W, et al. An economic analysis of transjugular intrahepatic portosystemic covered stent shunt for variceal bleeding and refractory ascites in a Spanish setting. Adv Ther 2023;40:3006-3020.
- 137. Mattock R, Tripathi D, O’Neill F, Craig J, Tanner J, Patch D, et al. Economic evaluation of covered stents for transjugular intrahepatic portosystemic stent shunt in patients with variceal bleeding and refractory ascites secondary to cirrhosis. BMJ Open Gastroenterol 2021;8:e000641.
- 138. Berry K, Lerrigo R, Liou IW, Ioannou GN. Association between transjugular intrahepatic portosystemic shunt and survival in patients with cirrhosis. Clin Gastroenterol Hepatol 2016;14:118-123.
- 139. Hosokawa I, Adam R, Allard MA, Pittau G, Vibert E, Cherqui D, et al. Outcomes of surgical shunts and transjugular intra-hepatic portasystemic stent shunts for complicated portal hypertension. Br J Surg 2017;104:443-451.
- 140. Xia Y, Tie J, Wang G, Wu H, Zhuge Y, Yuan X, et al. Benefits of TIPS for patients with large ascites preceding recurrent or refractory ascites: A multicenter cohort study. J Gastroenterol Hepatol 2025;40:1574-1585.
- 141. Bettinger D, Janoschke M, Jenkner C, Kaufmann M, van Gessel J, Otter HH, et al. Early implantation of a transjugular intrahepatic portosystemic shunt (TIPS) in patients with liver cirrhosis and ascites (eTIPS): a multicentre, randomised controlled trial. Trials 2025;26:385.
- 142. Seo JH, Kim SU, Park JY, Kim DY, Han KH, Chon CY, et al. Predictors of refractory ascites development in patients with hepatitis B virus-related cirrhosis hospitalized to control ascitic decompensation. Yonsei Med J 2013;54:145-153.
- 143. Heuman DM, Abou-Assi SG, Habib A, Williams LM, Stravitz RT, Sanyal AJ, et al. Persistent ascites and low serum sodium identify patients with cirrhosis and low MELD scores who are at high risk for early death. Hepatology 2004;40:802-810.
- 144. Durand F, Valla D. Assessment of prognosis of cirrhosis. Semin Liver Dis 2008;28:110-122.
- 145. Luca A, Angermayr B, Bertolini G, Koenig F, Vizzini G, Ploner M, et al. An integrated MELD model including serum sodium and age improves the prediction of early mortality in patients with cirrhosis. Liver Transpl 2007;13:1174-1180.
- 146. Ginès P, Arroyo V, Vargas V, Planas R, Casafont F, Panés J, et al. Paracentesis with intravenous infusion of albumin as compared with peritoneovenous shunting in cirrhosis with refractory ascites. N Engl J Med 1991;325:829-835.
- 147. Bureau C, Adebayo D, Chalret de Rieu M, Elkrief L, Valla D, Peck-Radosavljevic M, et al. Alfapump® system vs. large volume paracentesis for refractory ascites: A multicenter randomized controlled study. J Hepatol 2017;67:940-949.
- 148. Bellot P, Welker MW, Soriano G, von Schaewen M, Appenrodt B, Wiest R, et al. Automated low flow pump system for the treatment of refractory ascites: a multi-center safety and efficacy study. J Hepatol 2013;58:922-927.
- 149. Stirnimann G, Berg T, Spahr L, Zeuzem S, McPherson S, Lammert F, et al. Treatment of refractory ascites with an automated low-flow ascites pump in patients with cirrhosis. Aliment Pharmacol Ther 2017;46:981-991.
- 150. Simas D, Gonçalves A, Gomes P, Caetano I, Russo P, Atalaia-Martins C, et al. Long-term abdominal drains as a therapeutic option in refractory ascites - a systematic review. GE Port J Gastroenterol 2025;32:227-241.
- 151. Tergast TL, Griemsmann M, Stockhoff L, Heidrich B, Schirmer H, Lenzen H, et al. Home-based, tunnelled peritoneal drainage system as an alternative treatment option for patients with refractory ascites. Aliment Pharmacol Ther 2022;56:529-539.
- 152. Türk Y, Devecioğlu İ, Yıldızhan İ, Arslan BC, Arıbaş BK. Tunneled uncuffed pigtail drainage catheter placement in patients with refractory ascites or pleural effusion: A single-center experience. Cardiovasc Intervent Radiol 2022;45:1735-1741.
- 153. Stratmann K, Fitting D, Zeuzem S, Bojunga J, Trebicka J, Friedrich-Rust M, et al. Establishing an indwelling peritoneal catheter as a standard procedure for hospitalized patients with ascites: Retrospective data on feasibility, effectiveness and safety. United European Gastroenterol J 2019;7:673-681.
- 154. Kathpalia P, Bhatia A, Robertazzi S, Ahn J, Cohen SM, Sontag S, et al. Indwelling peritoneal catheters in patients with cirrhosis and refractory ascites. Intern Med J 2015;45:1026-1031.
- 155. Zaak D, Paquet KJ, Kuhn R. Prospective study comparing human albumin vs. reinfusion of ultrafiltrate-ascitic fluid after total paracentesis in cirrhotic patients with tense ascites. Z Gastroenterol 2001;39:5-10.
- 156. Graziotto A, Rossaro L, Inturri P, Salvagnini M. Reinfusion of concentrated ascitic fluid versus total paracentesis. A randomized prospective trial. Dig Dis Sci 1997;42:1708-1714.
- 157. Hanai T, Kawaratani H, Nagano J, Suii H, Sakamaki A, Arase Y, et al. Cell-free and concentrated ascites reinfusion therapy versus large-volume paracentesis for the treatment of cirrhotic patients with refractory ascites: A multicenter prospective observational study. Hepatol Res 2023;53:238-246.
- 158. Angeli P, Wong F, Watson H, Ginès P. CAPPS Investigators. Hyponatremia in cirrhosis: Results of a patient population survey. Hepatology 2006;44:1535-1542.
- 159. Jenq CC, Tsai MH, Tian YC, Chang MY, Lin CY, Lien JM, et al. Serum sodium predicts prognosis in critically ill cirrhotic patients. J Clin Gastroenterol 2010;44:220-226.
- 160. Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008;359:1018-1026.
- 161. Kim JH, Lee JS, Lee SH, Bae WK, Kim NH, Kim KA, et al. The association between the serum sodium level and the severity of complications in liver cirrhosis. Korean J Intern Med 2009;24:106-112.
- 162. Londoño MC, Guevara M, Rimola A, Navasa M, Taurà P, Mas A, et al. Hyponatremia impairs early posttransplantation outcome in patients with cirrhosis undergoing liver transplantation. Gastroenterology 2006;130:1135-1143.
- 163. Hackworth WA, Heuman DM, Sanyal AJ, Fisher RA, Sterling RK, Luketic VA, et al. Effect of hyponatraemia on outcomes following orthotopic liver transplantation. Liver Int 2009;29:1071-1077.
- 164. Alukal JJ, John S, Thuluvath PJ. Hyponatremia in cirrhosis: An update. Am J Gastroenterol 2020;115:1775-1785.
- 165. Ryu JY, Baek SH, Kim S. Evidence-based hyponatremia management in liver disease. Clin Mol Hepatol 2023;29:924-944.
- 166. Rondon-Berrios H, Velez JCQ. Hyponatremia in cirrhosis. Clin Liver Dis 2022;26:149-164.
- 167. Ahluwalia V, Heuman DM, Feldman G, Wade JB, Thacker LR, Gavis E, et al. Correction of hyponatraemia improves cognition, quality of life, and brain oedema in cirrhosis. J Hepatol 2015;62:75-82.
- 168. Ruf AE, Kremers WK, Chavez LL, Descalzi VI, Podesta LG, Villamil FG, et al. Addition of serum sodium into the MELD score predicts waiting list mortality better than MELD alone. Liver Transpl 2005;11:336-343.
- 169. Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581-1589.
- 170. Ge PS, Runyon BA. Treatment of patients with cirrhosis. N Engl J Med 2016;375:2104-2105.
- 171. Kim MY, Baik SK. Hyperdynamic circulation in patients with liver cirrhosis and portal hypertension. Korean J Gastroenterol 2009;54:143-148.
- 172. Arkenau HT, Stichtenoth DO, Frölich JC, Manns MP, Böker KH. Elevated nitric oxide levels in patients with chronic liver disease and cirrhosis correlate with disease stage and parameters of hyperdynamic circulation. Z Gastroenterol 2002;40:907-913.
- 173. Hébert RL, Jacobson HR, Breyer MD. PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation. Am J Physiol 1990;259:F318-F325.
- 174. Bichet D, Szatalowicz V, Chaimovitz C, Schrier RW. Role of vasopressin in abnormal water excretion in cirrhotic patients. Ann Intern Med 1982;96:413-417.
- 175. Verbalis JG, Goldsmith SR, Greenberg A, Korzelius C, Schrier RW, Sterns RH, et al. Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations. Am J Med 2013;126:S1-S42.
- 176. John S, Thuluvath PJ. Hyponatremia in cirrhosis: pathophysiology and management. World J Gastroenterol 2015;21:3197-3205.
- 177. Patel S, Nguyen DS, Rastogi A, Nguyen MK, Nguyen MK. Treatment of cirrhosis-associated hyponatremia with Midodrine and Octreotide. Front Med (Lausanne) 2017;4:17.
- 178. Sigal SH, Amin A, Chiodo JA, Sanyal A. Management strategies and outcomes for hyponatremia in cirrhosis in the hyponatremia registry. Can J Gastroenterol Hepatol 2018;2018:1579508.
- 179. Sinha VK, Ko B. Hyponatremia in cirrhosis--pathogenesis, treatment, and prognostic significance. Adv Chronic Kidney Dis 2015;22:361-367.
- 180. King JD, Rosner MH. Osmotic demyelination syndrome. Am J Med Sci 2010;339:561-567.
- 181. Berry K, Rubin JB, Lai JC. Osmotic demyelination syndrome in hospitalized patients with cirrhosis: analysis of the National Inpatient Sample (NIS). J Clin Gastroenterol 2022;56:280-283.
- 182. MacMillan TE, Shin S, Topf J, Kwan JL, Weinerman A, Tang T, et al. Osmotic demyelination syndrome in patients hospitalized with hyponatremia. NEJM Evid 2023;2:EVIDoa2200215.
- 183. Singh TD, Fugate JE, Rabinstein AA. Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21:1443-1450.
- 184. Leise M, Cárdenas A. Hyponatremia in cirrhosis: implications for liver transplantation. Liver Transpl 2018;24:1612-1621.
- 185. Bajaj JS, Tandon P, O’Leary JG, Biggins SW, Wong F, Kamath PS, et al. The impact of albumin use on resolution of hyponatremia in hospitalized patients with cirrhosis. Am J Gastroenterol 2018;113:1339.
- 186. Cárdenas A, Ginès P, Marotta P, Czerwiec F, Oyuang J, Guevara M, et al. Tolvaptan, an oral vasopressin antagonist, in the treatment of hyponatremia in cirrhosis. J Hepatol 2012;56:571-578.
- 187. Berl T, Quittnat-Pelletier F, Verbalis JG, Schrier RW, Bichet DG, Ouyang J, et al. Oral tolvaptan is safe and effective in chronic hyponatremia. J Am Soc Nephrol 2010;21:705-712.
- 188. Tang J, Wang Y, Han T, Mao Q, Cheng J, Ding H, et al. Tolvaptan therapy of Chinese cirrhotic patients with ascites after insufficient diuretic routine medication responses: a phase III clinical trial. BMC Gastroenterol 2020;20:391.
- 189. Suzuki Y, Naganuma A, Hoshino T, Hatanaka T, Ueno T, Namikawa M, et al. Tolvaptan reduces the required amount of albumin infusion in patients with decompensated cirrhosis with uncontrolled ascites: a multicenter retrospective propensity score-matched cohort study. Acta Gastroenterol Belg 2021;84:57-63.
- 190. Chai L, Li Z, Wang T, Wang R, Pinyopornpanish K, Cheng G, et al. Efficacy and safety of tolvaptan in cirrhotic patients: a systematic review and meta-analysis of randomized controlled trials. Expert Rev Gastroenterol Hepatol 2023;17:1041-1051.
- 191. European Association for the Study of the Liver. EASL clinical practice guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69:406-460.
- 192. Piano S, Fasolato S, Salinas F, Romano A, Tonon M, Morando F, et al. The empirical antibiotic treatment of nosocomial spontaneous bacterial peritonitis: Results of a randomized, controlled clinical trial. Hepatology 2016;63:1299-1309.
- 193. Rimola A, García-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:142-153.
- 194. Kim JJ, Tsukamoto MM, Mathur AK, Ghomri YM, Hou LA, Sheibani S, et al. Delayed paracentesis is associated with increased in-hospital mortality in patients with spontaneous bacterial peritonitis. Am J Gastroenterol 2014;109:1436-1442.
- 195. Wong CL, Holroyd-Leduc J, Thorpe KE, Straus SE. Does this patient have bacterial peritonitis or portal hypertension? How do I perform a paracentesis and analyze the results? JAMA 2008;299:1166-1178.
- 196. Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid culture technique. Gastroenterology 1988;95:1351-1355.
- 197. Kim SU, Kim DY, Lee CK, Park JY, Kim SH, Kim HM, et al. Ascitic fluid infection in patients with hepatitis B virus-related liver cirrhosis: culture-negative neutrocytic ascites versus spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2010;25:122-128.
- 198. Runyon BA. Monomicrobial nonneutrocytic bacterascites: a variant of spontaneous bacterial peritonitis. Hepatology 1990;12:710-715.
- 199. Pelletier G, Lesur G, Ink O, Hagege H, Attali P, Buffet C, et al. Asymptomatic bacterascites: is it spontaneous bacterial peritonitis? Hepatology 1991;14:112-115.
- 200. Soriano G, Castellote J, Alvarez C, Girbau A, Gordillo J, Baliellas C, et al. Secondary bacterial peritonitis in cirrhosis: a retrospective study of clinical and analytical characteristics, diagnosis and management. J Hepatol 2010;52:39-44.
- 201. Würstle S, Hapfelmeier A, Karapetyan S, Studen F, Isaakidou A, Schneider T, et al. Differentiation of spontaneous bacterial peritonitis from secondary peritonitis in patients with liver cirrhosis: retrospective multicentre study. Diagnostics (Basel) 2023;13:994.
- 202. Wu SS, Lin OS, Chen YY, Hwang KL, Soon MS, Keeffe EB, et al. Ascitic fluid carcinoembryonic antigen and alkaline phosphatase levels for the differentiation of primary from secondary bacterial peritonitis with intestinal perforation. J Hepatol 2001;34:215-221.
- 203. Arabi YM, Dara SI, Memish Z, Al Abdulkareem A, Tamim HM, Al-Shirawi N, et al. Antimicrobial therapeutic determinants of outcomes from septic shock among patients with cirrhosis. Hepatology 2012;56:2305-2315.
- 204. Yim HJ, Kim TH, Suh SJ, Yim SY, Jung YK, Seo YS, et al. Response-guided therapy with cefotaxime, ceftriaxone, or ciprofloxacin for spontaneous bacterial peritonitis: a randomized trial: a validation study of 2021 AASLD practice guidance for SBP. Am J Gastroenterol 2023;118:654-663.
- 205. Kim J, Kang CI, Gwak GY, Chung DR, Peck KR, Song JH, et al. Clinical impact of healthcare-associated acquisition in cirrhotic patients with community-onset spontaneous bacterial peritonitis. Korean J Intern Med 2020;35:215-221.
- 206. Na SH, Kim EJ, Nam EY, Song KH, Choe PG, Park WB, et al. Comparison of clinical characteristics and outcomes of spontaneous bacterial peritonitis and culture negative neutrocytic ascites. Scand J Gastroenterol 2017;52:199-203.
- 207. Kim JH, Jeon YD, Jung IY, Ahn MY, Ahn HW, Ahn JY, et al. Predictive factors of spontaneous bacterial peritonitis caused by gram-positive bacteria in patients with cirrhosis. Medicine (Baltimore) 2016;95:e3489.
- 208. Kim SW, Yoon JS, Park J, Jung YJ, Lee JS, Song J, et al. Empirical treatment with carbapenem vs third-generation cephalosporin for treatment of spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2021;19:976-986e5.
- 209. Kim T, Hong SI, Park SY, Jung J, Chong YP, Kim SH, et al. Clinical features and outcomes of spontaneous bacterial peritonitis caused by Streptococcus pneumoniae: a matched case-control study. Medicine (Baltimore) 2016;95:e3796.
- 210. Bae S, Kim T, Kim MC, Chong YP, Kim SH, Sung H, et al. Clinical characteristics and outcomes of spontaneous bacterial peritonitis caused by Enterobacter species versus Escherichia coli: a matched case-control study. BMC Infect Dis 2016;16:252.
- 211. Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis 2009;48:1230-1236.
- 212. Kim J, Kang CI, Joo EJ, Ha YE, Cho SY, Gwak GY, et al. Risk factor of community-onset spontaneous bacterial peritonitis caused by fluoroquinolone-resistant Escherichia coli in patients with cirrhosis. Liver Int 2014;34:695-699.
- 213. Song JY, Jung SJ, Park CW, Sohn JW, Kim WJ, Kim MJ, et al. Prognostic significance of infection acquisition sites in spontaneous bacterial peritonitis: nosocomial versus community acquired. J Korean Med Sci 2006;21:666-671.
- 214. Runyon BA, Akriviadis EA, Sattler FR, Cohen J. Ascitic fluid and serum cefotaxime and desacetyl cefotaxime levels in patients treated for bacterial peritonitis. Dig Dis Sci 1991;36:1782-1786.
- 215. Ricart E, Soriano G, Novella MT, Ortiz J, Sàbat M, Kolle L, et al. Amoxicillin-clavulanic acid versus cefotaxime in the therapy of bacterial infections in cirrhotic patients. J Hepatol 2000;32:596-602.
- 216. Iogna Prat L, Wilson P, Freeman SC, Sutton AJ, Cooper NJ, Roccarina D, et al. Antibiotic treatment for spontaneous bacterial peritonitis in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2019;9:CD013120.
- 217. Navasa M, Follo A, Llovet JM, Clemente G, Vargas V, Rimola A, et al. Randomized, comparative study of oral ofloxacin versus intravenous cefotaxime in spontaneous bacterial peritonitis. Gastroenterology 1996;111:1011-1017.
- 218. Runyon BA, McHutchison JG, Antillon MR, Akriviadis EA, Montano AA. Short-course versus long-course antibiotic treatment of spontaneous bacterial peritonitis. A randomized controlled study of 100 patients. Gastroenterology 1991;100:1737-1742.
- 219. Fong TL, Akriviadis EA, Runyon BA, Reynolds TB. Polymorphonuclear cell count response and duration of antibiotic therapy in spontaneous bacterial peritonitis. Hepatology 1989;9:423-426.
- 220. Goel A, Biewald M, Huprikar S, Schiano T, Im GY. A real-world evaluation of repeat paracentesis-guided management of spontaneous bacterial peritonitis. J Clin Gastroenterol 2017;51:278-284.
- 221. Huang CC, Chen YS, Toh HS, Lee YL, Liu YM, Ho CM, et al. Impact of revised CLSI breakpoints for susceptibility to third-generation cephalosporins and carbapenems among Enterobacteriaceae isolates in the Asia-Pacific region: results from the Study for Monitoring Antimicrobial Resistance Trends (SMART), 2002–2010. Int J Antimicr Agents 2012;40:Suppl. S4-S10.
- 222. Yoon YK, Kim J, Moon C, Lee MS, Hur J, Lee H, et al. Antimicrobial susceptibility of microorganisms isolated from patients with intraabdominal infection in Korea: a multicenter study. J Korean Med Sci 2019;34:e309.
- 223. Magiorakos AP, Srinivasan A, Carey RB, Carmeli Y, Falagas ME, Giske CG, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268-281.
- 224. Fernández J, Prado V, Trebicka J, Amoros A, Gustot T, Wiest R, et al. Multidrug-resistant bacterial infections in patients with decompensated cirrhosis and with acute-on-chronic liver failure in Europe. J Hepatol 2019;70:398-411.
- 225. Piano S, Singh V, Caraceni P, Maiwall R, Alessandria C, Fernandez J, et al. Epidemiology and effects of bacterial infections in patients with cirrhosis worldwide. Gastroenterology 2019;156:1368-1380e10.
- 226. Ariza X, Castellote J, Lora-Tamayo J, Girbau A, Salord S, Rota R, et al. Risk factors for resistance to ceftriaxone and its impact on mortality in community, healthcare and nosocomial spontaneous bacterial peritonitis. J Hepatol 2012;56:825-832.
- 227. Lutz P, Nischalke HD, Krämer B, Goeser F, Kaczmarek DJ, Schlabe S, et al. Antibiotic resistance in healthcare-related and nosocomial spontaneous bacterial peritonitis. Eur J Clin Invest 2017;47:44-52.
- 228. Yoon YK, Moon C, Kim J, Heo ST, Lee MS, Lee S, et al. Korean guidelines for use of antibiotics for intra-abdominal infections in adults. Infect Chemother 2022;54:812-853.
- 229. Doi Y. Treatment options for carbapenem-resistant gram-negative bacterial infections. Clin Infect Dis 2019;69:S565-S575.
- 230. Miller WR, Murray BE, Rice LB, Arias CA. Resistance in vancomycin-resistant enterococci. Infect Dis Clin North Am 2020;34:751-771.
- 231. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20:1495-1501.
- 232. Tandon P, Garcia-Tsao G. Renal dysfunction is the most important independent predictor of mortality in cirrhotic patients with spontaneous bacterial peritonitis. Clin Gastroenterol Hepatol 2011;9:260-265.
- 233. Bernard B, Grangé JD, Khac EN, Amiot X, Opolon P, Poynard T, et al. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta–analysis. Hepatology 1999;29:1655-1661.
- 234. Martínez J, Hernández-Gea V, Rodríguez-de-Santiago E, Téllez L, Procopet B, Giráldez Á, et al. Bacterial infections in patients with acute variceal bleeding in the era of antibiotic prophylaxis. J Hepatol 2021;75:342-350.
- 235. Zuo-Hua G, Chen-Chi T, Kuo-Chih T, Chih-Chun T, Yu-Hsi H, Tsung-Hsing H, et al. The effect of bacterial infections in cirrhotic patients with esophageal variceal bleeding. Ann Hepatol 2014;13:364-369.
- 236. Vivas S, Rodriguez M, Palacio MA, Linares A, Alonso JL, Rodrigo L, et al. Presence of bacterial infection in bleeding cirrhotic patients is independently associated with early mortality and failure to control bleeding. Dig Dis Sci 2001;46:2752-2757.
- 237. Soriano G, Guarner C, Tomás A, Villanueva C, Torras X, González D, et al. Norfloxacin prevents bacterial infection in cirrhotics with gastrointestinal hemorrhage. Gastroenterology 1992;103:1267-1272.
- 238. Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, et al. Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 2012;55:1551-1561.
- 239. Fernández J, Ruiz del Arbol L, Gómez C, Durandez R, Serradilla R, Guarner C, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049-1056 quiz 1285.
- 240. Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila F, Soares-Weiser K, Mendez-Sanchez N, Gluud C, et al. Metaanalysis: antibiotic prophylaxis for cirrhotic patients with upper gastrointestinal bleeding–an updated Cochrane review. Aliment Pharmacol Ther 2011;34:509-518.
- 241. Gao Y, Qian B, Zhang X, Liu H, Han T. Prophylactic antibiotics on patients with cirrhosis and upper gastrointestinal bleeding: A meta-analysis. PLoS One 2022;17:e0279496.
- 242. Gupta A, Agarwal S, Sharma S, Gopi S, Gunjan D, Saraya A, et al. Antibiotic prophylaxis to prevent infection in patients with Child–Pugh A cirrhosis with upper gastrointestinal bleed: an open label randomised controlled trial. Hepatol Int 2025;19:1162-1171.
- 243. Lo GH, Yeh JH, Tseng CH, Chen TH, Tai CM, Wang WL, et al. A noninferiority trial comparing 2 days vs 5 days of terlipressin and ceftriaxone in terms of 5-day rebleeding for patients with acute gastroesophageal variceal hemorrhage. Am J Gastroenterol 2024;119:1821-1830.
- 244. Prosty C, Noutsios D, Dubé LR, Baden R, Davar K, Freling S, et al. Prophylactic antibiotics for upper gastrointestinal bleeding in patients with cirrhosis: a systematic review and bayesian meta-analysis. JAMA Intern Med 2025;185:1194-1203.
- 245. Piano S, Bunchorntavakul C, Marciano S, Rajender Reddy K. Infections in cirrhosis. Lancet Gastroenterol Hepatol 2024;9:745-757.
- 246. Fernández J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818-824.
- 247. Lontos S, Shelton E, Angus PW, Vaughan R, Roberts SK, Gordon A, et al. A randomized controlled study of trimethoprim-sulfamethoxazole versus norfloxacin for the prevention of infection in cirrhotic patients. J Dig Dis 2014;15:260-267.
- 248. Thévenot T, Elkrief L, Bureau C, Bardou-Jacquet E, Rosa I, Nguyen-Khac E, et al. Effect of rifaximin in patients with severe cirrhosis and ascites: a randomized double-blind placebo-controlled clinical trial. J Hepatol 2025;83:1320-1327.
- 249. Hanouneh MA, Hanouneh IA, Hashash JG, Law R, Esfeh JM, Lopez R, et al. The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis. J Clin Gastroenterol 2012;46:709-715.
- 250. Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD, et al. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 2013;28:450-455.
- 251. Kang SH, Lee YB, Lee JH, Nam JY, Chang Y, Cho H, et al. Rifaximin treatment is associated with reduced risk of cirrhotic complications and prolonged overall survival in patients experiencing hepatic encephalopathy. Aliment Pharmacol Ther 2017;46:845-855.
- 252. Titó L, Rimola A, Ginès P, Llach J, Arroyo V, Rodés J, et al. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology 1988;8:27-31.
- 253. Abdel-Razik A, Abdelsalam M, Gad DF, Abdelwahab A, Tawfik M, Elzehery R, et al. Recurrence of spontaneous bacterial peritonitis in cirrhosis: novel predictors. Eur J Gastroenterol Hepatol 2020;32:718-726.
- 254. Ginés P, Rimola A, Planas R, Vargas V, Marco F, Almela M, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology 1990;12:716-724.
- 255. Praharaj DL, Premkumar M, Roy A, Verma N, Taneja S, Duseja A, et al. Rifaximin vs. norfloxacin for spontaneous bacterial peritonitis prophylaxis: a randomized controlled trial. J Clin Exp Hepatol 2022;12:336-342.
- 256. Elfert A, Abo Ali L, Soliman S, Ibrahim S, Abd-Elsalam S. Randomized-controlled trial of rifaximin versus norfloxacin for secondary prophylaxis of spontaneous bacterial peritonitis. Eur J Gastroenterol Hepatol 2016;28:1450-1454.
- 257. Mücke MM, Mayer A, Kessel J, Mücke VT, Bon D, Schwarzkopf K, et al. Quinolone and multidrug resistance predicts failure of antibiotic prophylaxis of spontaneous bacterial peritonitis. Clin Infect Dis 2020;70:1916-1924.
- 258. Badal BD, Silvey S, Dragilev L, O’Leary JG, Morgan TR, Cheung R, et al. Primary prophylaxis for spontaneous bacterial peritonitis is linked to antibiotic resistance in the Veterans Health Administration. Hepatology 2023;77:2030-2040.
- 259. Silvey S, Patel N, Tsai SY, Nadeem M, Sterling RK, Markley JD, et al. Higher rate of spontaneous bacterial peritonitis recurrence with secondary spontaneous bacterial peritonitis prophylaxis compared with no prophylaxis in 2 national cirrhosis cohorts. Am J Gastroenterol 2025;120:1066-1075.
- 260. Komolafe O, Roberts D, Freeman SC, Wilson P, Sutton AJ, Cooper NJ, et al. Antibiotic prophylaxis to prevent spontaneous bacterial peritonitis in people with liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2020;1:CD013125.
- 261. Mücke MM, Mücke VT, Graf C, Schwarzkopf KM, Ferstl PG, Fernandez J, et al. Efficacy of norfloxacin prophylaxis to prevent spontaneous bacterial peritonitis: a systematic review and meta-analysis. Clin Transl Gastroenterol 2020;11:e00223.
- 262. Crocombe D, O’Brien A. Antimicrobial prophylaxis in decompensated cirrhosis: friend or foe? Hepatol Commun 2023;7:e0228.
- 263. Markley JD, Bajaj JS. Rethinking antibiotic prophylaxis for spontaneous bacterial peritonitis in patients with cirrhosis: First, do no harm. Clin Infect Dis 2025;80:710-714.
- 264. Garcia-Tsao G, Parikh CR, Viola A. Acute kidney injury in cirrhosis. Hepatology 2008;48:2064-2077.
- 265. Choi YJ, Kim JH, Koo JK, Lee CI, Lee JY, Yang JH, et al. Prevalence of renal dysfunction in patients with cirrhosis according to ADQI-IAC working party proposal. Clin Mol Hepatol 2014;20:185-191.
- 266. Cárdenas A, Ginès P, Uriz J, Bessa X, Salmerón JM, Mas A, et al. Renal failure after upper gastrointestinal bleeding in cirrhosis: incidence, clinical course, predictive factors, and short-term prognosis. Hepatology 2001;34:671-676.
- 267. Belcher JM, Garcia-Tsao G, Sanyal AJ, Bhogal H, Lim JK, Ansari N, et al. Association of AKI with mortality and complications in hospitalized patients with cirrhosis. Hepatology 2013;57:753-762.
- 268. Bucsics T, Mandorfer M, Schwabl P, Bota S, Sieghart W, Ferlitsch A, et al. Impact of acute kidney injury on prognosis of patients with liver cirrhosis and ascites: a retrospective cohort study. J Gastroenterol Hepatol 2015;30:1657-1665.
- 269. Tsien CD, Rabie R, Wong F. Acute kidney injury in decompensated cirrhosis. Gut 2013;62:131-137.
- 270. Salerno F, Gerbes A, Ginès P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310-1318.
- 271. Lizaola-Mayo B, Vargas HE. Hepatorenal syndrome-acute kidney injury in liver transplantation. Clin Gastroenterol Hepa tol 2023;21:S20-S26.
- 272. Allegretti AS, Ortiz G, Wenger J, Deferio JJ, Wibecan J, Kalim S, et al. Prognosis of acute kidney injury and hepatorenal syndrome in patients with cirrhosis: a prospective cohort study. Int J Nephrol 2015;2015:108139.
- 273. Tan HK, Marquez M, Wong F, Renner EL. Pretransplant type 2 hepatorenal syndrome is associated with persistently impaired renal function after liver transplantation. Transplantation 2015;99:1441-1446.
- 274. Gonwa TA, Klintmalm GB, Levy M, Jennings LS, Goldstein RM, Husberg BS, et al. Impact of pretransplant renal function on survival after liver transplantation. Transplantation 1995;59:361-365.
- 275. Wong F. Acute kidney injury in liver cirrhosis: new definition and application. Clin Mol Hepatol 2016;22:415-422.
- 276. Orlando R, Floreani M, Padrini R, Palatini P. Evaluation of measured and calculated creatinine clearances as glomerular filtration markers in different stages of liver cirrhosis. Clin Nephrol 1999;51:341-347.
- 277. Sherman DS, Fish DN, Teitelbaum I. Assessing renal function in cirrhotic patients: problems and pitfalls. Am J Kidney Dis 2003;41:269-278.
- 278. Caregaro L, Menon F, Angeli P, Amodio P, Merkel C, Bortoluzzi A, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994;154:201-205.
- 279. Spencer K. Analytical reviews in clinical biochemistry: the estimation of creatinine. Ann Clin Biochem 1986;23(Pt 1):1-25.
- 280. Kim DJ, Kang HS, Choi HS, Cho HJ, Kim ES, Keum B, et al. Serum cystatin C level is a useful marker for the evaluation of renal function in patients with cirrhotic ascites and normal serum creatinine levels. Korean J Hepatol 2011;17:130-138.
- 281. Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut 2015;64:531-537.
- 282. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P, et al. Acute Dialysis Quality Initiative workgroup. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2004;8:R204-R212.
- 283. Mehta RL, Kellum JA, Shah SV, Molitoris BA, Ronco C, Warnock DG, et al. Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care 2007;11:R31.
- 284. Radhakrishnan J, Cattran DC. The KDIGO practice guideline on glomerulonephritis: reading between the (guide)lines-application to the individual patient. Kidney Int 2012;82:840-856.
- 285. Amathieu R, Al-Khafaji A, Sileanu FE, Foldes E, DeSensi R, Hilmi I, et al. Significance of oliguria in critically ill patients with chronic liver disease. Hepatology 2017;66:1592-1600.
- 286. Jin K, Murugan R, Sileanu FE, Foldes E, Priyanka P, Clermont G, et al. Intensive monitoring of urine output is associated with increased detection of acute kidney injury and improved outcomes. Chest 2017;152:972-979.
- 287. Trawalé JM, Paradis V, Rautou PE, Francoz C, Escolano S, Sallée M, et al. The spectrum of renal lesions in patients with cirrhosis: a clinicopathological study. Liver Int 2010;30:725-732.
- 288. Boyer TD, Sanyal AJ, Garcia-Tsao G, Blei A, Carl D, Bexon AS, et al. Predictors of response to terlipressin plus albumin in hepatorenal syndrome (HRS) type 1: relationship of serum creatinine to hemodynamics. J Hepatol 2011;55:315-321.
- 289. Rodríguez E, Elia C, Solà E, Barreto R, Graupera I, Andrealli A, et al. Terlipressin and albumin for type-1 hepatorenal syndrome associated with sepsis. J Hepatol 2014;60:955-961.
- 290. Philips CA, Maiwall R, Sharma MK, Jindal A, Choudhury AK, Kumar G, et al. Comparison of 5% human albumin and normal saline for fluid resuscitation in sepsis induced hypotension among patients with cirrhosis (FRISC study): a randomized controlled trial. Hepatol Int 2021;15:983-994.
- 291. Maiwall R, Kumar A, Pasupuleti SSR, Hidam AK, Tevethia H, Kumar G, et al. A randomized-controlled trial comparing 20% albumin to plasmalyte in patients with cirrhosis and sepsis-induced hypotension [ALPS trial]. J Hepatol 2022;77:670-682.
- 292. Schleicher EM, Karbannek H, Weinmann-Menke J, Galle PR, Stallmach A, Gairing SJ, et al. Effect of albumin treatment duration on response rates and outcomes in patients with cirrhosis and acute kidney injury. J Hepatol 2025;83:682-691.
- 293. Young P, Bailey M, Beasley R, Henderson S, Mackle D, McArthur C, et al. Effect of a Buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: the SPLIT randomized clinical trial. JAMA 2015;314:1701-1710.
- 294. Durand F, Kellum JA, Nadim MK. Fluid resuscitation in patients with cirrhosis and sepsis: A multidisciplinary perspective. J Hepatol 2023;79:240-246.
- 295. Warner NS, Cuthbert JA, Bhore R, Rockey DC. Acute kidney injury and chronic kidney disease in hospitalized patients with cirrhosis. J Investig Med 2011;59:1244-1251.
- 296. Schrier RW, Shchekochikhin D, Ginès P. Renal failure in cirrhosis: prerenal azotemia, hepatorenal syndrome and acute tubular necrosis. Nephrol Dial Transplant 2012;27:2625-2628.
- 297. Low G, Alexander GJ, Lomas DJ. Renal impairment in cirrhosis unrelated to hepatorenal syndrome. Can J Gastroenterol Hepatol 2015;29:253-257.
- 298. Schrier RW, Arroyo V, Bernardi M, Epstein M, Henriksen JH, Rodés J, et al. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis. Hepatology 1988;8:1151-1157.
- 299. Ruiz-del-Arbol L, Urman J, Fernández J, González M, Navasa M, Monescillo A, et al. Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis. Hepatology 2003;38:1210-1218.
- 300. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Ginès P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439-447.
- 301. Arroyo V, Colmenero J. Ascites and hepatorenal syndrome in cirrhosis: pathophysiological basis of therapy and current management. J Hepatol 2003;38:Suppl 1. S69-S89.
- 302. Wong F. Recent advances in our understanding of hepatorenal syndrome. Nat Rev Gastroenterol Hepatol 2012;9:382-391.
- 303. Arroyo V, Angeli P, Moreau R, Jalan R, Clària J, Trebicka J, et al. The systemic inflammation hypothesis: Towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis. J Hepatol 2021;74:670-685.
- 304. Trebicka J, Amoros A, Pitarch C, Titos E, Alcaraz-Quiles J, Schierwagen R, et al. Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis. Front Immunol 2019;10:476.
- 305. Zhang IW, Curto A, López-Vicario C, Casulleras M, Duran-Güell M, Flores-Costa R, et al. Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure. J Hepatol 2022;76:93-106.
- 306. Krag A, Bendtsen F, Henriksen JH, Møller S. Low cardiac output predicts development of hepatorenal syndrome and survival in patients with cirrhosis and ascites. Gut 2010;59:105-110.
- 307. Ghallab A, González D, Strängberg E, Hofmann U, Myllys M, Hassan R, et al. Inhibition of the renal apical sodium dependent bile acid transporter prevents cholemic nephropathy in mice with obstructive cholestasis. J Hepatol 2024;80:268-281.
- 308. Angeli P, Ginès P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. J Hepatol 2015;62:968-974.
- 309. Alsaad AA, Wadei HM. Fractional excretion of sodium in hepatorenal syndrome: Clinical and pathological correlation. World J Hepatol 2016;8:1497-1501.
- 310. Belcher JM, Sanyal AJ, Peixoto AJ, Perazella MA, Lim J, Thiessen-Philbrook H, et al. Kidney biomarkers and differential diagnosis of patients with cirrhosis and acute kidney injury. Hepatology 2014;60:622-632.
- 311. Patidar KR, Kang L, Bajaj JS, Carl D, Sanyal AJ. Fractional excretion of urea: A simple tool for the differential diagnosis of acute kidney injury in cirrhosis. Hepatology 2018;68:224-233.
- 312. Carvounis CP, Nisar S, Guro-Razuman S. Significance of the fractional excretion of urea in the differential diagnosis of acute renal failure. Kidney Int 2002;62:2223-2229.
- 313. Juanola A, Ma AT, de Wit K, Gananandan K, Roux O, Zaccherini G, et al. Novel prognostic biomarkers in decompensated cirrhosis: a systematic review and meta-analysis. Gut 2023;73:156-165.
- 314. Lee HA, Seo YS. Current knowledge about biomarkers of acute kidney injury in liver cirrhosis. Clin Mol Hepatol 2022;28:31-46.
- 315. Singapura P, Ma TW, Sarmast N, Gonzalez SA, Durand F, Maiwall R, et al. Estimating glomerular filtration rate in cirrhosis using creatinine-based and cystatin C-based equations: systematic review and meta-analysis. Liver Transpl 2021;27:1538-1552.
- 316. Markwardt D, Holdt L, Steib C, Benesic A, Bendtsen F, Bernardi M, et al. Plasma cystatin C is a predictor of renal dysfunction, acute-on-chronic liver failure, and mortality in patients with acutely decompensated liver cirrhosis. Hepatology 2017;66:1232-1241.
- 317. Maiwall R, Kumar A, Bhardwaj A, Kumar G, Bhadoria AS, Sarin SK, et al. Cystatin C predicts acute kidney injury and mortality in cirrhotics: A prospective cohort study. Liver Int 2018;38:654-664.
- 318. Seo YS, Park SY, Kim MY, Kim SG, Park JY, Yim HJ, et al. Serum cystatin C level: An excellent predictor of mortality in patients with cirrhotic ascites. J Gastroenterol Hepatol 2018;33:910-917.
- 319. Francoz C, Nadim MK, Durand F. Kidney biomarkers in cirrhosis. J Hepatol 2016;65:809-824.
- 320. Belcher JM, Garcia-Tsao G, Sanyal AJ, Thiessen-Philbrook H, Peixoto AJ, Perazella MA, et al. Urinary biomarkers and progression of AKI in patients with cirrhosis. Clin J Am Soc Nephrol 2014;9:1857-1867.
- 321. Ariza X, Solà E, Elia C, Barreto R, Moreira R, Morales-Ruiz M, et al. Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis. PLoS One 2015;10:e0128145.
- 322. Gambino C, Piano S, Stenico M, Tonon M, Brocca A, Calvino V, et al. Diagnostic and prognostic performance of urinary neutrophil gelatinase-associated lipocalin in patients with cirrhosis and acute kidney injury. Hepatology 2023;77:1630-1638.
- 323. George R, Sonika U, Mahajan B, Sharma A, Dalal A, Sachdeva S, et al. Diagnostic utility of urine neutrophil gelatinase-associated lipocalin and renal resistive index in patients of decompensated cirrhosis with acute kidney injury. Dig Liver Dis 2023;55:1230-1235.
- 324. Huelin P, Solà E, Elia C, Solé C, Risso A, Moreira R, et al. Neutrophil gelatinase-associated lipocalin for assessment of acute kidney injury in cirrhosis: a prospective study. Hepatology 2019;70:319-333.
- 325. Allegretti AS, Parada XV, Endres P, Zhao S, Krinsky S, St Hillien SA, et al. Urinary NGAL as a diagnostic and prognostic marker for acute kidney injury in cirrhosis: a prospective study. Clin Transl Gastroenterol 2021;12:e00359.
- 326. Treeprasertsuk S, Wongkarnjana A, Jaruvongvanich V, Sallapant S, Tiranathanagul K, Komolmit P, et al. Urine neutrophil gelatinase-associated lipocalin: a diagnostic and prognostic marker for acute kidney injury (AKI) in hospitalized cirrhotic patients with AKI-prone conditions. BMC Gastroenterol 2015;15:140.
- 327. Qasem AA, Farag SE, Hamed E, Emara M, Bihery A, Pasha H, et al. Urinary biomarkers of acute kidney injury in patients with liver cirrhosis. ISRN Nephrol 2014;2014:376795.
- 328. Hamdy HS, El-Ray A, Salaheldin M, Lasheen M, Aboul-Ezz M, Abdel-Moaty AS, et al. Urinary neutrophil gelatinase-associated lipocalin in cirrhotic patients with acute kidney injury. Ann Hepatol 2018;17:624-630.
- 329. Fagundes C, Pépin MN, Guevara M, Barreto R, Casals G, Solà E, et al. Urinary neutrophil gelatinase-associated lipocalin as biomarker in the differential diagnosis of impairment of kidney function in cirrhosis. J Hepatol 2012;57:267-273.
- 330. Udgirkar S, Rathi P, Sonthalia N, Chandnani S, Contractor Q, Thanage R, et al. Urinary neutrophil gelatinase-associated lipocalin determines short-term mortality and type of acute kidney injury in cirrhosis. JGH Open 2020;4:970-977.
- 331. Altran WS, de Sousa LF, Dos Santos Cortinhas R, Ponce D. The role of urinary biomarkers in the diagnosis of acute kidney injury in patients with liver cirrhosis. Sci Rep 2025;15:11575.
- 332. Ma AT, Solé C, Juanola A, Escudé L, Napoleone L, Avitabile E, et al. Prospective validation of the EASL management algorithm for acute kidney injury in cirrhosis. J Hepatol 2024;81:441-450.
- 333. Patidar KR, Cullaro G, Naved MA, Kabir S, Grama A, Orman ES, et al. Prognostic significance of acute kidney injury stage 1B in hospitalized patients with cirrhosis: A US nationwide study. Liver Transpl 2024;30:244-253.
- 334. Khatua CR, Sahu SK, Barik RK, Pradhan S, Panigrahi S, Mishra D, et al. Validation of international club of ascites subclassification of stage 1 acute kidney injury in chronic liver disease. JGH Open 2019;3:290-294.
- 335. Huelin P, Piano S, Solà E, Stanco M, Solé C, Moreira R, et al. Validation of a staging system for acute kidney injury in patients with cirrhosis and association with acute-on-chronic liver failure. Clin Gastroenterol Hepatol 2017;15:438-445e5.
- 336. Fagundes C, Barreto R, Guevara M, Garcia E, Solà E, Rodríguez E, et al. A modified acute kidney injury classification for diagnosis and risk stratification of impairment of kidney function in cirrhosis. J Hepatol 2013;59:474-481.
- 337. Wan YM, Wu HM, Li YH, Huang SQ, Yin HJ, Xu Y, et al. The mortality risk of acute kidney injury stage 1A and 1B in cirrhosis: a systematic review and meta-analysis. J Clin Exp Hepatol 2025;15:103154.
- 338. Macedo E, Mehta RL. Prerenal failure: from old concepts to new paradigms. Curr Opin Crit Care 2009;15:467-473.
- 339. Wong F, Pappas SC, Curry MP, Reddy KR, Rubin RA, Porayko MK, et al. Terlipressin plus albumin for the treatment of type 1 hepatorenal syndrome. N Engl J Med 2021;384:818-828.
- 340. Wong F. Drug insight: the role of albumin in the management of chronic liver disease. Nat Clin Pract Gastroenterol Hepatol 2007;4:43-51.
- 341. Angeli P, Labenz C, Piano S, Juanola A, Krag A, Caraceni P, et al. Albumin infusion in hepatorenal syndrome-acute kidney injury: New evidence challenges recent consensus. J Hepatol 2025;83:800-802.
- 342. Garcia-Martinez R, Caraceni P, Bernardi M, Gines P, Arroyo V, Jalan R, et al. Albumin: pathophysiologic basis of its role in the treatment of cirrhosis and its complications. Hepatology 2013;58:1836-1846.
- 343. Garcia-Martinez R, Noiret L, Sen S, Mookerjee R, Jalan R. Albumin infusion improves renal blood flow autoregulation in patients with acute decompensation of cirrhosis and acute kidney injury. Liver Int 2015;35:335-343.
- 344. Boyer TD, Sanyal AJ, Wong F, Frederick RT, Lake JR, O’Leary JG, et al. Terlipressin plus albumin is more effective than albumin alone in improving renal function in patients with cirrhosis and hepatorenal syndrome type 1. Gastroenterology 2016;150:1579-1589e2.
- 345. Jamil K, Pappas SC, Devarakonda KR. In vitro binding and receptor-mediated activity of terlipressin at vasopressin receptors V(1) and V(2). J Exp Pharmacol 2017;10:1-7.
- 346. Kulkarni AV, Arab JP, Premkumar M, Benítez C, Tirumalige Ravikumar S, Kumar P, et al. Terlipressin has stood the test of time: Clinical overview in 2020 and future perspectives. Liver Int 2020;40:2888-2905.
- 347. Sanyal AJ, Boyer TD, Frederick RT, Wong F, Rossaro L, Araya V, et al. Reversal of hepatorenal syndrome type 1 with terlipressin plus albumin vs. placebo plus albumin in a pooled analysis of the OT-0401 and REVERSE randomised clinical studies. Aliment Pharmacol Ther 2017;45:1390-1402.
- 348. Best LM, Freeman SC, Sutton AJ, Cooper NJ, Tng EL, Csenar M, et al. Treatment for hepatorenal syndrome in people with decompensated liver cirrhosis: a network meta-analysis. Cochrane Database Syst Rev 2019;9:CD013103.
- 349. Thomson MJ, Taylor A, Sharma P, Lok AS, Tapper EB. Limited progress in hepatorenal syndrome (HRS) reversal and survival 2002–2018: a systematic review and meta-analysis. Dig Dis Sci 2020;65:1539-1548.
- 350. Pitre T, Kiflen M, Helmeczi W, Dionne JC, Rewa O, Bagshaw SM, et al. The comparative effectiveness of vasoactive treatments for hepatorenal syndrome: a systematic review and network meta-analysis. Crit Care Med 2022;50:1419-1429.
- 351. Facciorusso A, Chandar AK, Murad MH, Prokop LJ, Muscatiello N, Kamath PS, et al. Comparative efficacy of pharmacological strategies for management of type 1 hepatorenal syndrome: a systematic review and network meta-analysis. Lancet Gastroenterol Hepatol 2017;2:94-102.
- 352. Shang Y, Wang C, Lu H, Chai L, Xu W, Bernardi M, et al. Incidence and type of adverse events in patients with cirrhosis receiving terlipressin: A systematic review and meta-analysis. Hepatol Commun 2024;8:e0526.
- 353. Cavallin M, Piano S, Romano A, Fasolato S, Frigo AC, Benetti G, et al. Terlipressin given by continuous intravenous infusion versus intravenous boluses in the treatment of hepatorenal syndrome: A randomized controlled study. Hepatology 2016;63:983-992.
- 354. Cullaro G, Allegretti AS, Patidar KR, Jamil K, Velez JCQ. The relationship between mean arterial pressure and terlipressin in hepatorenal syndrome-acute kidney injury reversal: A post hoc analysis. Hepatology 2026;83:94-104.
- 355. Bellomo R, Giantomasso DD. Noradrenaline and the kidney: friends or foes? Crit Care 2001;5:294-298.
- 356. Olson JC, Subramanian RM. Comparative efficacy of terlipressin and norepinephrine for treatment of hepatorenal syndrome-acute kidney injury: A systematic review and meta-analysis. PLoS One 2024;19:e0296690.
- 357. Nassar Junior AP, Farias AQ, D’ Albuquerque LA, Carrilho FJ, Malbouisson LM. Terlipressin versus norepinephrine in the treatment of hepatorenal syndrome: a systematic review and meta-analysis. PLoS One 2014;9:e107466.
- 358. US Food and Drug Administration. Drugs@FDA: FDA-Approved Drugs. ProAmatine (midodrine hydrochloride). FDA website. https://www.fda.gov/drugsatfda. Accessed 3 Jun 2026..
- 359. Esrailian E, Pantangco ER, Kyulo NL, Hu KQ, Runyon BA. Octreotide/Midodrine therapy significantly improves renal function and 30-day survival in patients with type 1 hepatorenal syndrome. Dig Dis Sci 2007;52:742-748.
- 360. Skagen C, Einstein M, Lucey MR, Said A. Combination treatment with octreotide, midodrine, and albumin improves survival in patients with type 1 and type 2 hepatorenal syndrome. J Clin Gastroenterol 2009;43:680-685.
- 361. Cavallin M, Kamath PS, Merli M, Fasolato S, Toniutto P, Salerno F, et al. Terlipressin plus albumin versus midodrine and octreotide plus albumin in the treatment of hepatorenal syndrome: A randomized trial. Hepatology 2015;62:567-574.
- 362. Nadim MK, Durand F, Kellum JA, Levitsky J, O’Leary JG, Karvellas CJ, et al. Management of the critically ill patient with cirrhosis: A multidisciplinary perspective. J Hepatol 2016;64:717-735.
- 363. Song T, Rössle M, He F, Liu F, Guo X, Qi X, et al. Transjugular intrahepatic portosystemic shunt for hepatorenal syndrome: a systematic review and meta-analysis. Dig Liver Dis 2018;50:323-330.
- 364. Bureau C, Thabut D, Oberti F, Dharancy S, Carbonell N, Bouvier A, et al. Transjugular intrahepatic portosystemic shunts with covered stents increase transplant-free survival of patients with cirrhosis and recurrent ascites. Gastroenterology 2017;152:157-163.
- 365. Gonzalez-Garay AG, Serralde-Zúñiga AE, Velasco Hidalgo L, Flores García NC, Aguirre-Salgado MI. Transjugular intrahepatic portosystemic shunts for adults with hepatorenal syndrome. Cochrane Database Syst Rev 2024;1:CD011039.
- 366. Wong F, Sniderman K, Liu P, Allidina Y, Sherman M, Blendis L, et al. Transjugular intrahepatic portosystemic stent shunt: effects on hemodynamics and sodium homeostasis in cirrhosis and refractory ascites. Ann Intern Med 1995;122:816-822.
- 367. Trebicka J. Emergency TIPS in a Child-Pugh B patient: When does the window of opportunity open and close? J Hepatol 2017;66:442-450.
- 368. Wong LP, Blackley MP, Andreoni KA, Chin H, Falk RJ, Klemmer PJ, et al. Survival of liver transplant candidates with acute renal failure receiving renal replacement therapy. Kidney Int 2005;68:362-370.
- 369. Diaz PM, Saly DL, Horick N, Petrosyan R, Gitto Z, Indriolo T, et al. Prognosis of transplant-ineligible patients with cirrhosis and acute kidney injury who initiate renal replacement therapy. Dig Dis Sci 2024;69:3710-3720.
- 370. Nair S, Verma S, Thuluvath PJ. Pretransplant renal function predicts survival in patients undergoing orthotopic liver transplantation. Hepatology 2002;35:1179-1185.
- 371. Marik PE, Wood K, Starzl TE. The course of type 1 hepatorenal syndrome post liver transplantation. Nephrol Dial Transplant 2006;21:478-482.
- 372. Wong F, Leung W, Al Beshir M, Marquez M, Renner EL. Outcomes of patients with cirrhosis and hepatorenal syndrome type 1 treated with liver transplantation. Liver Transpl 2015;21:300-307.
- 373. Nadim MK, Kellum JA, Davenport A, Wong F, Davis C, Pannu N, et al. Hepatorenal syndrome: the 8th International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 2012;16:R23.
- 374. Boyer TD, Sanyal AJ, Garcia-Tsao G, Regenstein F, Rossaro L, Appenrodt B, et al. Impact of liver transplantation on the survival of patients treated for hepatorenal syndrome type 1. Liver Transpl 2011;17:1328-1332.
- 375. Elia C, Graupera I, Barreto R, Solà E, Moreira R, Huelin P, et al. Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: a case-control study. J Hepatol 2015;63:593-600.
- 376. Sola-Vera J, Miñana J, Ricart E, Planella M, González B, Torras X, et al. Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites. Hepatology 2003;37:1147-1153.
- 377. Sigal SH, Stanca CM, Fernandez J, Arroyo V, Navasa M. Restricted use of albumin for spontaneous bacterial peritonitis. Gut 2007;56:597-599.
- 378. Dong T, Aronsohn A, Gautham Reddy K, Te HS. Rifaximin decreases the incidence and severity of acute kidney injury and hepatorenal syndrome in cirrhosis. Dig Dis Sci 2016;61:3621-3626.
- 379. Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK, et al. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol 2013;108:1458-1463.
- 380. Cardenas A, Kelleher T, Chopra S. Review article: hepatic hydrothorax. Aliment Pharmacol Ther 2004;20:271-279.
- 381. Roussos A, Philippou N, Mantzaris GJ, Gourgouliannis KI. Hepatic hydrothorax: pathophysiology diagnosis and management. J Gastroenterol Hepatol 2007;22:1388-1393.
- 382. Huang PM, Chang YL, Yang CY, Lee YC. The morphology of diaphragmatic defects in hepatic hydrothorax: thoracoscopic finding. J Thorac Cardiovasc Surg 2005;130:141-145.
- 383. Machicao VI, Balakrishnan M, Fallon MB. Pulmonary complications in chronic liver disease. Hepatology 2014;59:1627-1637.
- 384. Badillo R, Rockey DC. Hepatic hydrothorax: clinical features, management, and outcomes in 77 patients and review of the literature. Medicine (Baltimore) 2014;93:135-142.
- 385. Gurung P, Goldblatt M, Huggins JT, Doelken P, Nietert PJ, Sahn SA, et al. Pleural fluid analysis and radiographic, sonographic, and echocardiographic characteristics of hepatic hydrothorax. Chest 2011;140:448-453.
- 386. Vidyani A, Sibarani CI, Widodo B, Purbayu H, Thamrin H, Miftahussurur M, et al. Diagnosis and management of hepatic hydrothorax. Korean J Gastroenterol 2024;83:45-53.
- 387. Lv Y, Han G, Fan D. Hepatic hydrothorax. Ann Hepatol 2018;17:33-46.
- 388. Xiol X, Castellví JM, Guardiola J, Sesé E, Castellote J, Perelló A, et al. Spontaneous bacterial empyema in cirrhotic patients: a prospective study. Hepatology 1996;23:719-723.
- 389. Abbasi A, Bhutto AR, Alam MT, Aurangzaib M, Masroor M. Frequency of hepatic hydrothorax and its association with Child Pugh class in liver cirrhosis patients. J Coll Physicians Surg Pak 2016;26:566-569.
- 390. Makhlouf HA, Morsy KH, Makhlouf NA, Eldin EN, Khairy M. Spontaneous bacterial empyema in patients with liver cirrhosis in Upper Egypt: prevalence and causative organisms. Hepatol Int 2013;7:274-279.
- 391. Chen CH, Shih CM, Chou JW, Liu YH, Hang LW, Hsia TC, et al. Outcome predictors of cirrhotic patients with spontaneous bacterial empyema. Liver Int 2011;31:417-424.
- 392. Lai YK, Eiger G, Fischer RA. Point: does spontaneous bacterial empyema occur? Yes. Chest 2015;147:1207-1208.
- 393. O’Leary JG, Rajender Reddy K, Tandon P, Biggins SW, Wong F, Kamath PS, et al. Increased risk of ACLF and inpatient mortality in hospitalized patients with cirrhosis and hepatic hydrothorax. Dig Dis Sci 2021;66:3612-3618.
- 394. Osman KT, Naritsin A, Amuchi B, Qamar AA. Liver transplantation for refractory hepatic hydrothorax is associated with a greater survival benefit compared to other complications of cirrhosis. Liver Transpl 2024;30:142-150.
- 395. Hassaballa AS, Mostafa A, Hikal T, Elnori A, Elsayed HH. Pleural manometry during thoracocentesis in patients with malignant pleural effusion: A randomized controlled trial. Can J Respir Ther 2023;59:33-44.
- 396. Ault MJ, Rosen BT, Scher J, Feinglass J, Barsuk JH. Thoracentesis outcomes: a 12-year experience. Thorax 2015;70:127-132.
- 397. Gilbert CR, Shojaee S, Maldonado F, Yarmus LB, Bedawi E, Feller-Kopman D, et al. Pleural interventions in the management of hepatic hydrothorax. Chest 2022;161:276-283.
- 398. Xiol X, Castellote J, Cortes-Beut R, Delgado M, Guardiola J, Sesé E, et al. Usefulness and complications of thoracentesis in cirrhotic patients. Am J Med 2001;111:67-69.
- 399. Gordon FD, Anastopoulos HT, Crenshaw W, Gilchrist B, McEniff N, Falchuk KR, et al. The successful treatment of symptomatic, refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt. Hepatology 1997;25:1366-1369.
- 400. Jeffries MA, Kazanjian S, Wilson M, Punch J, Fontana RJ. Transjugular intrahepatic portosystemic shunts and liver transplantation in patients with refractory hepatic hydrothorax. Liver Transpl Surg 1998;4:416-423.
- 401. Ditah IC, Al Bawardy BF, Saberi B, Ditah C, Kamath PS. Transjugular intrahepatic portosystemic stent shunt for medically refractory hepatic hydrothorax: a systematic review and cumulative meta-analysis. World J Hepatol 2015;7:1797-1806.
- 402. Spencer EB, Cohen DT, Darcy MD. Safety and efficacy of transjugular intrahepatic portosystemic shunt creation for the treatment of hepatic hydrothorax. J Vasc Interv Radiol 2002;13:385-390.
- 403. Young S, Bermudez J, Zhang L, Rostambeigi N, Golzarian J. Transjugular intrahepatic portosystemic shunt (TIPS) placement: A comparison of outcomes between patients with hepatic hydrothorax and patients with refractory ascites. Diagn Interv Imaging 2019;100:303-308.
- 404. Lee HL, Lee SW. The role of transjugular intrahepatic portosystemic shunt in patients with portal hypertension: advantages and pitfalls. Clin Mol Hepatol 2022;28:121-134.
- 405. Hung ML, Lee EW. Role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension: review and update of the literature. Clin Liver Dis 2019;23:737-754.
- 406. Siegerstetter V, Deibert P, Ochs A, Olschewski M, Blum HE, Rössle M, et al. Treatment of refractory hepatic hydrothorax with transjugular intrahepatic portosystemic shunt: long-term results in 40 patients. Eur J Gastroenterol Hepatol 2001;13:529-534.
- 407. Dhanasekaran R, West JK, Gonzales PC, Subramanian R, Parekh S, Spivey JR, et al. Transjugular intrahepatic portosystemic shunt for symptomatic refractory hepatic hydrothorax in patients with cirrhosis. Am J Gastroenterol 2010;105:635-641.
- 408. Jindal A, Mukund A, Kumar G, Sarin SK. Efficacy and safety of transjugular intrahepatic portosystemic shunt in difficult-to-manage hydrothorax in cirrhosis. Liver Int 2019;39:2164-2173.
- 409. Huang PM, Kuo SW, Chen JS, Lee JM. Thoracoscopic mesh repair of diaphragmatic defects in hepatic hydrothorax: a 10-year experience. Ann Thorac Surg 2016;101:1921-1927.
- 410. Jung Y, Song SY, Na KJ, Chon SH, Jun CH, Choi SK, et al. Minimally invasive surgical strategy for refractory hepatic hydrothorax. Eur J Cardiothorac Surg 2020;57:881-887.
- 411. Shojaee S, Rahman N, Haas K, Kern R, Leise M, Alnijoumi M, et al. Indwelling tunneled pleural catheters for refractory hepatic hydrothorax in patients with cirrhosis: a multicenter study. Chest 2019;155:546-553.
- 412. Avula A, Acharya S, Anwar S, Narula N, Chalhoub M, Maroun R, et al. Indwelling pleural catheter (IPC) for the management of hepatic hydrothorax: the known and the unknown. J Bronchology Interv Pulmonol 2022;29:179-185.
- 413. Kniese C, Diab K, Ghabril M, Bosslet G. Indwelling pleural catheters in hepatic hydrothorax: a single-center series of outcomes and complications. Chest 2019;155:307-314.
- 414. Chen A, Massoni J, Jung D, Crippin J. Indwelling tunneled pleural catheters for the management of hepatic hydrothorax. A pilot study. Ann Am Thorac Soc 2016;13:862-866.
- 415. Hou F, Qi X, Guo X. Effectiveness and safety of pleurodesis for hepatic hydrothorax: a systematic review and meta-analysis. Dig Dis Sci 2016;61:3321-3334.
- 416. Lee WJ, Kim HJ, Park JH, Park DI, Cho YK, Sohn CI, et al. Chemical pleurodesis for the management of refractory hepatic hydrothorax in patients with decompensated liver cirrhosis. Korean J Hepatol 2011;17:292-298.
- 417. Milanez de Campos JR, Filho LO, de Campos Werebe E, Sette H, Fernandez A, Filomeno LT, et al. Thoracoscopy and talc poudrage in the management of hepatic hydrothorax. Chest 2000;118:13-17.
- 418. Orman ES, Lok AS. Outcomes of patients with chest tube insertion for hepatic hydrothorax. Hepatol Int 2009;3:582-586.
- 419. Liu LU, Haddadin HA, Bodian CA, Sigal SH, Korman JD, Bodenheimer HC, et al. Outcome analysis of cirrhotic patients undergoing chest tube placement. Chest 2004;126:142-148.
- 420. Banini BA, Alwatari Y, Stovall M, Ogden N, Gershman E, Shah RD, et al. Multidisciplinary management of hepatic hydrothorax in 2020: An evidence-based review and guidance. Hepatology 2020;72:1851-1863.
- 421. Singh A, Bajwa A, Shujaat A. Evidence-based review of the management of hepatic hydrothorax. Respiration 2013;86:155-173.
- 422. Shojaee S, Khalid M, Kallingal G, Kang L, Rahman N. Repeat thoracentesis in hepatic hydrothorax and non-hepatic hydrothorax effusions: a case-control study. Respiration 2018;96:330-337.
- 423. Han SK, Kang SH, Kim MY, Na SK, Kim T, Lee M, et al. Outcome of intermittent thoracentesis versus pigtail catheter drainage for hepatic hydrothorax. J Clin Med 2022;11:5480.
- 424. Sharaf-Eldin M, Bediwy AS, Kobtan A, Abd-Elsalam S, El-Kalla F, Mansour L, et al. Pigtail catheter: a less invasive option for pleural drainage in Egyptian patients with recurrent hepatic hydrothorax. Gastroenterol Res Pract 2016;2016:4013052.
- 425. Yoon JH, Kim HJ, Jun CH, Cho SB, Jung Y, Choi SK, et al. Various treatment modalities in hepatic hydrothorax: what is safe and effective? Yonsei Med J 2019;60:944-951.
- 426. Belghiti J, Durand F. Abdominal wall hernias in the setting of cirrhosis. Semin Liver Dis 1997;17:219-226.
- 427. Triantos CK, Kehagias I, Nikolopoulou V, Burroughs AK. Incarcerated umbilical hernia after large volume paracentesis for refractory ascites. J Gastrointestin Liver Dis 2010;19:245.
- 428. Chu KM, McCaughan GW. Iatrogenic incarceration of umbilical hernia in cirrhotic patients with ascites. Am J Gastroenterol 1995;90:2058-2059.
- 429. de Goede B, van Kempen BJ, Polak WG, de Knegt RJ, Schouten JN, Lange JF, et al. Umbilical hernia management during liver transplantation. Hernia 2013;17:515-519.
- 430. Hew S, Yu W, Robson S, Starkey G, Testro A, Fink M, et al. Safety and effectiveness of umbilical hernia repair in patients with cirrhosis. Hernia 2018;22:759-765.
- 431. Oh HK, Kim H, Ryoo S, Choe EK, Park KJ. Inguinal hernia repair in patients with cirrhosis is not associated with increased risk of complications and recurrence. World J Surg 2011;35:1229-1233 discussion 1234.
- 432. Eker HH, van Ramshorst GH, de Goede B, Tilanus HW, Metselaar HJ, de Man RA, et al. A prospective study on elective umbilical hernia repair in patients with liver cirrhosis and ascites. Surgery 2011;150:542-546.
- 433. Odom SR, Gupta A, Talmor D, Novack V, Sagy I, Evenson AR, et al. Emergency hernia repair in cirrhotic patients with ascites. J Trauma Acute Care Surg 2013;75:404-409.
- 434. Hur YH, Kim JC, Kim DY, Kim SK, Park CY. Inguinal hernia repair in patients with liver cirrhosis accompanied by ascites. J Korean Surg Soc 2011;80:420-425.
- 435. Ecker BL, Bartlett EK, Hoffman RL, Karakousis GC, Roses RE, Morris JB, et al. Hernia repair in the presence of ascites. J Surg Res 2014;190:471-477.
- 436. Cho HC, Jung HY, Sinn DH, Choi MS, Koh KC, Paik SW, et al. Mortality after surgery in patients with liver cirrhosis: comparison of Child-Turcotte-Pugh, MELD and MELDNa score. Eur J Gastroenterol Hepatol 2011;23:51-59.
- 437. Cho SW, Bhayani N, Newell P, Cassera MA, Hammill CW, Wolf RF, et al. Umbilical hernia repair in patients with signs of portal hypertension: surgical outcome and predictors of mortality. Arch Surg 2012;147:864-869.
- 438. Pinheiro RS, Andraus W, Waisberg DR, Nacif LS, Ducatti L, Rocha-Santos V, et al. Abdominal hernias in cirrhotic patients: Surgery or conservative treatment? Results of a prospective cohort study in a high volume center: Cohort study. Ann Med Surg (Lond) 2019;49:9-13.
- 439. Bronswijk M, Jaekers J, Vanella G, Struyve M, Miserez M, van der Merwe S, et al. Umbilical hernia repair in patients with cirrhosis: who, when and how to treat. Hernia 2022;26:1447-1457.
- 440. Runyon BA, Juler GL. Natural history of repaired umbilical hernias in patients with and without ascites. Am J Gastroenterol 1985;80:38-39.
- 441. Johnson KM, Newman KL, Berry K, Itani K, Wu P, Kamath PS, et al. Risk factors for adverse outcomes in emergency versus nonemergency open umbilical hernia repair and opportunities for elective repair in a national cohort of patients with cirrhosis. Surgery 2022;172:184-192.
- 442. Gray SH, Vick CC, Graham LA, Finan KR, Neumayer LA, Hawn MT, et al. Umbilical herniorrhapy in cirrhosis: improved outcomes with elective repair. J Gastrointest Surg 2008;12:675-681.
- 443. Choi SB, Hong KD, Lee JS, Han HJ, Kim WB, Song TJ, et al. Management of umbilical hernia complicated with liver cirrhosis: an advocate of early and elective herniorrhaphy. Dig Liver Dis 2011;43:991-995.
- 444. Telem DA, Schiano T, Divino CM. Complicated hernia presentation in patients with advanced cirrhosis and refractory ascites: management and outcome. Surgery 2010;148:538-543.
- 445. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol 2008;64:1147-1161.
- 446. Elbekai RH, Korashy HM, El-Kadi AO. The effect of liver cirrhosis on the regulation and expression of drug metabolizing enzymes. Curr Drug Metab 2004;5:157-167.
- 447. Villeneuve JP, Verbeeck RK, Wilkinson GR, Branch RA. Furosemide kinetics and dynamics in patients with cirrhosis. Clin Pharmacol Ther 1986;40:14-20.
- 448. Lewis JH, Stine JG. Review article: prescribing medications in patients with cirrhosis - a practical guide. Aliment Pharmacol Ther 2013;37:1132-1156.
- 449. Chalasani N, Gorski JC, Patel NH, Hall SD, Galinsky RE. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology 2001;34:1103-1108.
- 450. Vuppalanchi R, Juluri R, Ghabril M, Kim S, Thong N, Gorski JC, et al. Drug-induced QT prolongation in cirrhotic patients with transjugular intrahepatic portosystemic shunt. J Clin Gastroenterol 2011;45:638-642.
- 451. Liu ZX, Kaplowitz N. Role of innate immunity in acetaminophen-induced hepatotoxicity. Expert Opin Drug Metab Toxicol 2006;2:493-503.
- 452. Zimmerman HJ. The spectrum of hepatotoxicity. Perspect Biol Med 1968;12:135-161.
- 453. Chandok N, Watt KD. Pain management in the cirrhotic patient: the clinical challenge. Mayo Clin Proc 2010;85:451-458.
- 454. Manyike PT, Kharasch ED, Kalhorn TF, Slattery JT. Contribution of CYP2E1 and CYP3A to acetaminophen reactive metabolite formation. Clin Pharmacol Ther 2000;67:275-282.
- 455. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure. Hepatology 1995;22:767-773.
- 456. Benson GD. Acetaminophen in chronic liver disease. Clin Pharmacol Ther 1983;33:95-101.
- 457. Andreasen PB, Hutters L. Paracetamol (acetaminophen) clearance in patients with cirrhosis of the liver. Acta Med Scand Suppl 1979;624:99-105.
- 458. McGill MR, James LP, McCullough SS, Moran JH, Mathews SE, Peterson EC, et al. Short-term safety of repeated acetaminophen use in patients with compensated cirrhosis. Hepatol Commun 2022;6:361-373.
- 459. Fenkel JM, Coron RN, Daskalakis C, Vega M, Rossi S, Herrine SK, et al. Over-the-counter analgesics in cirrhotic patients: a case-control study examining the risk of hospitalization for liver-associated events. Scand J Gastroenterol 2010;45:1101-1109.
- 460. Khalid SK, Lane J, Navarro V, Garcia-Tsao G. Use of over-the-counter analgesics is not associated with acute decompensation in patients with cirrhosis. Clin Gastroenterol Hepatol 2009;7:994-999 quiz 913–914.
- 461. American Geriatrics Society Panel on Pharmacological Management of Persistent Pain in Older Persons. Pharmacological management of persistent pain in older persons. J Am Geriatr Soc 2009;57:1331-1346.
- 462. Hong YM, Yoon KT, Heo J, Woo HY, Lim W, An DS, et al. The prescription pattern of acetaminophen and non-steroidal anti-inflammatory drugs in patients with liver cirrhosis. J Korean Med Sci 2016;31:1604-1610.
- 463. Williams RL, Upton RA, Cello JP, Jones RM, Blitstein M, Kelly J, et al. Naproxen disposition in patients with alcoholic cirrhosis. Eur J Clin Pharmacol 1984;27:291-296.
- 464. Bosilkovska M, Walder B, Besson M, Daali Y, Desmeules J. Analgesics in patients with hepatic impairment: pharmacology and clinical implications. Drugs 2012;72:1645-1669.
- 465. Ackerman Z, Cominelli F, Reynolds TB. Effect of misoprostol on ibuprofen-induced renal dysfunction in patients with decompensated cirrhosis: results of a double-blind placebo-controlled parallel group study. Am J Gastroenterol 2002;97:2033-2039.
- 466. Clària J, Kent JD, López-Parra M, Escolar G, Ruiz-Del-Arbol L, Ginès P, et al. Effects of celecoxib and naproxen on renal function in nonazotemic patients with cirrhosis and ascites. Hepatology 2005;41:579-587.
- 467. De Lédinghen V, Heresbach D, Fourdan O, Bernard P, Liebaert-Bories MP, Nousbaum JB, et al. Anti-inflammatory drugs and variceal bleeding: a case-control study. Gut 1999;44:270-273.
- 468. Luo JC, Leu HB, Hou MC, Huang CC, Lin HC, Lee FY, et al. Cirrhotic patients at increased risk of peptic ulcer bleeding: a nationwide population-based cohort study. Aliment Pharmacol Ther 2012;36:542-550.
- 469. Lee YC, Chang CH, Lin JW, Chen HC, Lin MS, Lai MS, et al. Non-steroidal anti-inflammatory drugs use and risk of upper gastrointestinal adverse events in cirrhotic patients. Liver Int 2012;32:859-866.
- 470. Guevara M, Abecasis R, Terg R. Effect of celecoxib on renal function in cirrhotic patients with ascites. A pilot study. Scand J Gastroenterol 2004;39:385-386.
- 471. Hur C, Chan AT, Tramontano AC, Gazelle GS. Coxibs versus combination NSAID and PPI therapy for chronic pain: an exploration of the risks, benefits, and costs. Ann Pharmacother 2006;40:1052-1063.
- 472. Chen YF, Jobanputra P, Barton P, Bryan S, Fry-Smith A, Harris G, et al. Cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs (etodolac, meloxicam, celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib) for osteoarthritis and rheumatoid arthritis: a systematic review and economic evaluation. Health Technol Assess 2008;12:1-278. iii.
- 473. Peng JK, Hepgul N, Higginson IJ, Gao W. Symptom prevalence and quality of life of patients with end-stage liver disease: A systematic review and meta-analysis. Palliat Med 2019;33:24-36.
- 474. Hasselström J, Eriksson S, Persson A, Rane A, Svensson JO, Säwe J, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990;29:289-297.
- 475. Tallgren M, Olkkola KT, Seppälä T, Höckerstedt K, Lindgren L. Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation. Clin Pharmacol Ther 1997;61:655-661.
- 476. Haberer JP, Schoeffler P, Couderc E, Duvaldestin P. Fentanyl pharmacokinetics in anaesthetized patients with cirrhosis. Br J Anaesth 1982;54:1267-1270.
- 477. Smith HS. Opioid metabolism. Mayo Clin Proc 2009;84:613-624.
- 478. Durnin C, Hind ID, Ghani SP, Yates DB, Molz KH. Pharmacokinetics of oral immediate-release hydromorphone (Dilaudid IR) in subjects with moderate hepatic impairment. Proc West Pharmacol Soc 2001;44:83-84.
- 479. Kotb HI, Fouad IA, Fares KM, Mostafa MG, Abd El-Rahman AM. Pharmacokinetics of oral tramadol in patients with liver cancer. J Opioid Manag 2008;4:99-104.
- 450. Nelson EM, Philbrick AM. Avoiding serotonin syndrome: the nature of the interaction between tramadol and selective serotonin reuptake inhibitors. Ann Pharmacother 2012;46:1712-1716.
- 481. Spies PE, Pot JLWH, Willems RPJ, Bos JM, Kramers C. Interaction between tramadol and selective serotonin reuptake inhibitors: are doctors aware of potential risks in their prescription practice? Eur J Hosp Pharm 2017;24:124-127.
- 482. de Franchis R, Bosch J, Garcia-Tsao G, Reiberger T, Ripoll C, et al. Baveno VII Faculty. Baveno VII - Renewing consensus in portal hypertension. J Hepatol 2022;76:959-974.
- 483. Villanueva C, Torres F, Sarin SK, Shah HA, Tripathi D, Brujats A, et al. Carvedilol reduces the risk of decompensation and mortality in patients with compensated cirrhosis in a competing-risk meta-analysis. J Hepatol 2022;77:1014-1025.
- 484. Villanueva C, Albillos A, Genescà J, Garcia-Pagan JC, Calleja JL, Aracil C, et al. β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial. Lancet 2019;393:1597-1608.
- 485. Turco L, Taru MG, Vitale G, Stefanescu H, Mirici Cappa F, Berardi S, et al. Beta-blockers lower first decompensation in patients with cirrhosis and enduring portal hypertension after etiological treatment. Clin Gastroenterol Hepatol 2025;23:987-996e8.
- 486. Liu C, You H, Zeng QL, Wong YJ, Wang B, Grgurevic I, et al. Carvedilol to prevent hepatic decompensation of cirrhosis in patients with clinically significant portal hypertension stratified by new non-invasive model (CHESS2306). Clin Mol Hepatol 2025;31:105-118.
- 487. Rodrigues SG, Mendoza YP, Bosch J. Beta-blockers in cirrhosis: Evidence-based indications and limitations. JHEP Rep 2019;2:100063.
- 488. Ge PS, Runyon BA. The changing role of beta-blocker therapy in patients with cirrhosis. J Hepatol 2014;60:643-653.
- 489. Sinha R, Lockman KA, Mallawaarachchi N, Robertson M, Plevris JN, Hayes PC, et al. Carvedilol use is associated with improved survival in patients with liver cirrhosis and ascites. J Hepatol 2017;67:40-46.
- 490. Tergast TL, Kimmann M, Laser H, Gerbel S, Manns MP, Cornberg M, et al. Systemic arterial blood pressure determines the therapeutic window of non-selective beta blockers in decompensated cirrhosis. Aliment Pharmacol Ther 2019;50:696-706.
- 491. Tittanegro T, China L, Forrest E, Kallis Y, Ryder SD, Wright G, et al. Use of non-selective B-blockers is safe in hospitalised decompensated cirrhosis patients and exerts a potential anti-inflammatory effect: Data from the ATTIRE trial. EClinicalMedicine 2022;55:101716.
- 492. Sersté T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cirrhosis and refractory ascites. Hepatology 2010;52:1017-1022.
- 493. Sersté T, Francoz C, Durand F, Rautou PE, Melot C, Valla D, et al. Beta-blockers cause paracentesis-induced circulatory dysfunction in patients with cirrhosis and refractory ascites: a cross-over study. J Hepatol 2011;55:794-799.
- 494. Wu Y, Ge X, Wang SN, Zhang CQ. Olmesartan improves hepatic sinusoidal remodeling in mice with carbon tetrachlorideinduced liver fibrosis. Biomed Res Int 2022;2022:4710993.
- 495. Tandon P, Abraldes JG, Berzigotti A, Garcia-Pagan JC, Bosch J. Renin–angiotensin–aldosterone inhibitors in the reduction of portal pressure: A systematic review and meta-analysis. J Hepatol 2010;53:273-282.
- 496. Daskalopoulos G, Pinzani M, Murray N, Hirschberg R, Zipser RD. Effects of captopril on renal function in patients with cirrhosis and ascites. J Hepatol 1987;4:330-336.
- 497. Gentilini P, Romanelli RG, La Villa G, Maggiore Q, Pesciullesi E, Cappelli G, et al. Effects of low-dose captopril on renal hemodynamics and function in patients with cirrhosis of the liver. Gastroenterology 1993;104:588-594.
- 498. Chen Y, Zhai D, Shen J, Hu W. Impact of renin-angiotensin-aldosterone system inhibitors on liver-related events and mortality in patients with cirrhosis: a meta-analysis of real-world evidence. J Gastroenterol Hepatol 2025;40:2139-2147.
- 499. González-Abraldes J, Albillos A, Bañares R, Del Arbol LR, Moitinho E, Rodríguez C, et al. Randomized comparison of long-term losartan versus propranolol in lowering portal pressure in cirrhosis. Gastroenterology 2001;121:382-388.
- 500. Schepke M, Werner E, Biecker E, Schiedermaier P, Heller J, Neef M, et al. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology 2001;121:389-395.
- 501. Schneider AW, Kalk JF, Klein CP. Effect of losartan, an angiotensin II receptor antagonist, on portal pressure in cirrhosis. Hepatology 1999;29:334-339.
- 502. Yao H, Zhang C. Angiotensin II receptor blockers for the treatment of portal hypertension in patients with liver cirrhosis: a systematic review and meta-analysis of randomized controlled trials. Ir J Med Sci 2018;187:925-934.
- 503. Tergast TL, Griemsmann M, Wedemeyer H, Cornberg M, Maasoumy B. Effects of renin-angiotensin inhibitors on renal function and the clinical course in patients with decompensated cirrhosis. Sci Rep 2023;13:17486.
- 504. Björnsson E, Jacobsen EI, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol 2012;56:374-380.
- 505. Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 2004;10:1018-1023.
- 506. Athyros VG, Tziomalos K, Gossios TD, Griva T, Anagnostis P, Kargiotis K, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis. Lancet 2010;376:1916-1922.
- 507. Lewis JH, Mortensen ME, Zweig S, Fusco MJ, Medoff JR, Belder R, et al. Efficacy and safety of high-dose pravastatin in hypercholesterolemic patients with well-compensated chronic liver disease: Results of a prospective, randomized, double-blind, placebo-controlled, multicenter trial. Hepatology 2007;46:1453-1463.
- 508. Gu Y, Yang X, Liang H, Li D. Comprehensive evaluation of effects and safety of statin on the progression of liver cirrhosis: a systematic review and meta-analysis. BMC Gastroenterol 2019;19:231.
- 509. Singh KN, Mejia Perez LK, Singh A, Carey W. 965 safety of statins in decompensated cirrhosis in patients listed for liver transplantation. Am J Gastroenterol 2019;114:S561-S562.
- 510. Abraldes JG, Villanueva C, Aracil C, Turnes J, Hernandez-Guerra M, Genesca J, et al. Addition of Simvastatin to standard therapy for the prevention of variceal rebleeding does not reduce rebleeding but increases survival in patients with cirrhosis. Gastroenterology 2016;150:1160-1170e3.
- 511. Kim RG, Loomba R, Prokop LJ, Singh S. Statin use and risk of cirrhosis and related complications in patients with chronic liver diseases: a systematic review and meta-analysis. Clin Gastroenterol Hepatol 2017;15:1521-1530e8.
- 512. Kaplan DE, Serper MA, Mehta R, Fox R, John B, Aytaman A, et al. Effects of hypercholesterolemia and statin exposure on survival in a large national cohort of patients with cirrhosis. Gastroenterology 2019;156:1693-1706e12.
- 513. Mahmud N, Chapin S, Goldberg DS, Reddy KR, Taddei TH, Kaplan DE, et al. Statin exposure is associated with reduced development of acute-on-chronic liver failure in a Veterans Affairs cohort. J Hepatol 2022;76:1100-1108.
- 514. Singh S, Singh PP, Singh AG, Murad MH, Sanchez W. Statins are associated with a reduced risk of hepatocellular cancer: a systematic review and meta-analysis. Gastroenterology 2013;144:323-332.
- 515. Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, et al. Statin use decreases the incidence of hepatocellular carcinoma: an updated meta-analysis. Cancers (Basel) 2020;12:874.
- 516. Yun B, Ahn SH, Yoon JH, Kim BK. Statin use and risk of progression to liver cirrhosis in chronic hepatitis B independent of conventional risk factors: A nationwide study. Hepatol Commun 2022;6:2455-2464.
- 517. Cho Y, Kim MS, Nam CM, Kang ES. Statin use is associated with decreased hepatocellular carcinoma recurrence in liver transplant patients. Sci Rep 2019;9:1467.
- 518. Sharpton SR, Loomba R. Emerging role of statin therapy in the prevention and management of cirrhosis, portal hypertension, and HCC. Hepatology 2023;78:1896-1906.
- 519. Tsai PC, Huang CF, Yeh ML, Hsieh MH, Kuo HT, Hung CH, et al. Metformin and statins reduce hepatocellular carcinoma risk in chronic hepatitis C patients with failed antiviral therapy. Clin Mol Hepatol 2024;30:468-486.
- 520. Kronborg TM, Schierwagen R, Trošt K, Gao Q, Moritz T, Bendtsen F, et al. Atorvastatin for patients with cirrhosis. A randomized, placebo-controlled trial. Hepatol Commun 2023;7:e0332.
- 521. Pose E, Jiménez C, Zaccherini G, Campion D, Piano S, Uschner FE, et al. Simvastatin and rifaximin in decompensated cirrhosis: A randomized clinical trial. JAMA 2025;333:864-874.
- 522. Dam G, Vilstrup H, Watson H, Jepsen P. Proton pump inhibitors as a risk factor for hepatic encephalopathy and spontaneous bacterial peritonitis in patients with cirrhosis with ascites. Hepatology 2016;64:1265-1272.
- 523. Goel GA, Deshpande A, Lopez R, Hall GS, van Duin D, Carey WD, et al. Increased rate of spontaneous bacterial peritonitis among cirrhotic patients receiving pharmacologic acid suppression. Clin Gastroenterol Hepatol 2012;10:422-427.
- 524. Bajaj JS, Ratliff SM, Heuman DM, Lapane KL. Proton pump inhibitors are associated with a high rate of serious infections in veterans with decompensated cirrhosis. Aliment Pharmacol Ther 2012;36:866-874.
- 525. Tsai CF, Chen MH, Wang YP, Chu CJ, Huang YH, Lin HC, et al. Proton pump inhibitors increase risk for hepatic encephalopathy in patients with cirrhosis in A population study. Gastroenterology 2017;152:134-141.
- 526. Wong ZY, Koh JH, Muthiah M, Koh B, Ong EYH, Ong CEY, et al. Proton pump inhibitors increases longitudinal risk of mortality, decompensation, and infection in cirrhosis: a metaanalysis. Dig Dis Sci 2024;69:289-297.
- 527. Terg R, Casciato P, Garbe C, Cartier M, Stieben T, Mendizabal M, et al. Proton pump inhibitor therapy does not increase the incidence of spontaneous bacterial peritonitis in cirrhosis: a multicenter prospective study. J Hepatol 2015;62:1056-1060.
- 528. China L, Tittanegro T, Crocombe D, Forrest E, Kallis Y, Ryder SD, et al. Investigating potential confounding by indication when considering the association between proton pump inhibitor use, infection, hepatic encephalopathy and mortality in hospitalised decompensated cirrhosis: a post-hoc analysis of the ATTIRE trial. EClinicalMedicine 2023;58:101924.
- 529. Gairing SJ, Mangini C, Zarantonello L, Jonasson E, Dobbermann H, Sultanik P, et al. Proton pump inhibitor use and risk of hepatic encephalopathy: A multicentre study. JHEP Rep 2024;6:101104.
- 530. Mahmud N, Serper M, Taddei TH, Kaplan DE. The association between proton pump inhibitor exposure and key liver-related outcomes in patients with cirrhosis: A Veterans affairs cohort study. Gastroenterology 2022;163:257-269e6.
- 531. Weersink RA, Bouma M, Burger DM, Drenth JPH, Harkes-Idzinga SF, Hunfeld NGM, et al. Safe use of proton pump inhibitors in patients with cirrhosis. Br J Clin Pharmacol 2018;84:1806-1820.
- 532. Kim MG, Im YJ, Lee JH, Kim EY, Yeom SW, Kim JS, et al. Comparison of hepatotoxicity of tegoprazan, a novel potassium-competitive acid blocker, with proton pump inhibitors using real-world data: A nationwide cohort study. Front Med (Lausanne) 2023;9:1076356.
- 533. Kim GH, Choi MG, Kim JI, Lee ST, Chun HJ, Lee KL, et al. Efficacy and safety of fexuprazan in patients with acute or chronic gastritis. Gut Liver 2023;17:884-893.
- 534. Kawaguchi T, Taniguchi E, Itou M, Sakata M, Sumie S, Sata M, et al. Insulin resistance and chronic liver disease. World J Hepatol 2011;3:99-107.
- 535. Ampuero J, Ranchal I, Nuñez D, Díaz-Herrero Mdel M, Maraver M, del Campo JA, et al. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy. PLoS One 2012;7:e49279.
- 536. Yen FS, Huang YH, Hou MC, Hwu CM, Lo YR, Shin SJ, et al. Metformin use and cirrhotic decompensation in patients with type 2 diabetes and liver cirrhosis. Br J Clin Pharmacol 2022;88:311-322.
- 537. Ou SM, Shih CJ, Chao PW, Chu H, Kuo SC, Lee YJ, et al. Effects on clinical outcomes of adding dipeptidyl peptidase-4 inhibitors versus sulfonylureas to metformin therapy in patients with type 2 diabetes mellitus. Ann Intern Med 2015;163:663-672.
- 538. Hatorp V, Walther KH, Christensen MS, Haug-Pihale G. Single-dose pharmacokinetics of repaglinide in subjects with chronic liver disease. J Clin Pharmacol 2000;40:142-152.
- 539. Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004;27:256-263.
- 540. Yen FS, Wei JC, Chiu LT, Hsu CC, Hou MC, Hwu CM, et al. Thiazolidinediones were associated with higher risk of cardiovascular events in patients with type 2 diabetes and cirrhosis. Liver Int 2021;41:110-122.
- 541. Chung W, Promrat K, Wands J. Clinical implications, diagnosis, and management of diabetes in patients with chronic liver diseases. World J Hepatol 2020;12:533-557.
- 542. Gentile S, Guarino G, Romano M, Alagia IA, Fierro M, Annunziata S, et al. A randomized controlled trial of acarbose in hepatic encephalopathy. Clin Gastroenterol Hepatol 2005;3:184-191.
- 543. Bouchi R, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, et al. Dipeptidyl peptidase 4 inhibitors attenuates the decline of skeletal muscle mass in patients with type 2 diabetes. Diabetes Metab Res Rev 2018;34:e2970.
- 544. Abu-Hammour MN, Abdel-Razeq R, Vignarajah A, Khedraki R, Sims OT, Vigneswaramoorthy N, et al. Sodium-glucose cotransporter 2 inhibitors and serious liver events in patients with cirrhosis. JAMA Netw Open 2025;8:e2518470.
- 545. Huynh DJ, Renelus BD, Jamorabo DS. Reduced mortality and morbidity associated with metformin and SGLT2 inhibitor therapy in patients with type 2 diabetes mellitus and cirrhosis. BMC Gastroenterol 2023;23:450.
- 546. Montalvo-Gordon I, Chi-Cervera LA, García-Tsao G. Sodiumglucose cotransporter 2 inhibitors ameliorate ascites and peripheral edema in patients with cirrhosis and diabetes. Hepatology 2020;72:1880-1882.
- 547. Choi J, Fulop D, Nguyen VH, Przybyszewski E, Song J, Carroll A, et al. Comparative risk of fibrosis progression with SGLT2 vs. DPP-4 inhibitors in MASLD and T2DM with low-to-intermediate fibrosis. Clin Mol Hepatol 2026;32:305-317.
, Moon Young Kim6
