Ascites in acute A window into disease severity

Authors: Enver Zerem, Dina Zerem, Šeila Vila, Sanja Bajgorić

Abstract

Acute pancreatitis (AP) is a complex and potentially life-threatening inflammatory condition with a highly variable clinical course, ranging from mild, self-limiting episodes to severe necrotizing forms. Among its common complications ascites has traditionally been viewed as a passive byproduct of peritoneal inflammation and enzymatic leakage with limited diagnostic or prognostic utility. However, growing evidence challenges this perspective, suggesting that ascitic fluid in AP represents a dynamic and clinically meaningful component of disease progression. In this editorial we reflected on the findings presented by Rao et al, who highlighted the diagnostic, prognostic, and therapeutic significance of ascitic fluid in AP. Easily accessible markers such as lactate dehydrogenase may provide early prognostic insight while emerging molecular biomarkers and cytokine profiles offer promise for more precise risk stratification and individualized therapy. We argue that the systematic evaluation of ascitic fluid should be integrated into the clinical management of moderate to severe AP. Incorporating ascites analysis into standard diagnostic protocols may enhance early risk assessment, inform therapeutic decisions, and ultimately improve patient outcomes. Ascitic fluid should be recognized as a clinically valuable marker and an important source of information in the evolving landscape of AP care.

Core Tip: There is increasing evidence that ascites in acute pancreatitis is more than an epiphenomenon. It reflects disease severity, provides actionable clinical information on inflammatory burden, vascular permeability, and risk of complications, and may serve as a target for personalized therapeutic strategies. Its biochemical and cellular composition can further support early risk stratification and guide treatment decisions.

INTRODUCTION

In their recent article published in the World Journal of Gastroenterology, Rao et al[1] emphasized the prognostic value of ascitic fluid analysis in acute pancreatitis (AP), suggesting that early assessment may help identify patients at increased risk for severe complications and mortality[1]. While we agree with these conclusions, our clinical experience indicates that the implications of ascites in AP extend beyond prognostication, influencing disease course, severity stratification, and therapeutic strategy[2-4].

AP is one of the most common gastrointestinal emergencies and is characterized by a broad clinical spectrum ranging from mild, self-limiting inflammation to severe necrotizing disease with systemic complications. Current scoring systems (such as Ranson, APACHE II, Glasgow, Balthazar, BISAP, and others) offer valuable but often incomplete predictions of disease severity, especially in dynamic or emergent settings. Although advances in biomarkers and imaging modalities have enhanced early risk assessment, there remains a need for accessible, reliable, and clinically actionable indicators of disease progression[1-5].

Among emerging prognostic markers ascitic fluid has gained increasing recognition as both a radiological and biochemical marker of disease severity. Despite its omission from classification systems like the revised Atlanta Criteria, early ascites is consistently associated with pancreatic necrosis, infection, multiorgan failure, and adverse clinical outcomes[2,6-9]. Moreover, its biochemical profile including elevated amylase, proteins, and proinflammatory mediators may reflect both local and systemic inflammatory burden[8-12].

In our clinical practice we have observed that the systematic evaluation of ascites, particularly in the first 72 hours, provides actionable information that often precedes changes in conventional scoring systems. This editorial aimed to synthesize the existing evidence while also advocating for a more proactive approach to ascitic fluid analysis, framing it not just as a prognostic tool but as a guide for therapeutic strategy.

PATHOPHYSIOLOGY AND PROGNOSTIC SIGNIFICANCE OF ASCITES IN AP

Ascitic fluid accumulation in AP reflects both localized pancreatic damage and systemic inflammatory activation. Although not currently included in standardized scoring systems for disease severity, the presence of ascites is increasingly recognized as a marker of more severe disease and a potential contributor to clinical deterioration[6,10-13].

The development of ascitic fluid in AP is multifactorial. A central mechanism involves increased vascular permeability, triggered by intense systemic inflammation and pancreatic tissue autodigestion. Premature activation of digestive enzymes (such as trypsin, phospholipase A2, and elastase) leads to disruption of acinar cells and surrounding peripancreatic tissues, promoting the leakage of enzyme-rich exudate into the peritoneal cavity. Simultaneously, elevated levels of proinflammatory cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α) increase endothelial permeability and exacerbate fluid extravasation[11-15]. Structural complications, such as rupture of pancreatic pseudocysts (PPC) or pancreatic duct disruption may also result in persistent or high-volume ascites, particularly in the later stages of disease[4,16-18]. It is also important to note that the etiology of AP may influence the characteristics of ascites. For example, bile-stained ascites is more common in biliary pancreatitis, hemorrhagic ascites in alcoholic pancreatitis, and large-volume sterile effusions in hypertriglyceridemic AP. However, most published studies have not stratified outcomes by AP subtype, highlighting an area for future research[18-20].

In hemorrhagic forms of AP, vascular necrosis or erosion may result in blood-stained ascites, which are often associated with greater disease severity and higher mortality[19]. Biochemically, the ascitic fluid is typically exudative and is characterized by high protein content, elevated concentrations of pancreatic enzymes (particularly amylase) and variable concentrations of inflammatory mediators.

Recent clinical studies have demonstrated a strong correlation between the presence and volume of ascitic fluid detected on contrast-enhanced CT (CECT) and adverse outcomes, including pancreatic necrosis, persistent organ failure, and mortality[20,21]. According to several studies, ascites has emerged as an independent predictor of mortality and is linked with longer hospital stays, a greater need for intensive care, and a more complicated clinical course[20-23]. These findings suggest that the identification of ascites early in the course of AP could enhance prognostic assessment and help guide clinical management.

Given the accumulating evidence, ascites in AP should not be considered a benign or incidental finding. Instead, it reflects active disease progression and may provide valuable information for early therapeutic decisions, including the need for intensified monitoring, more targeted fluid resuscitation, or the application of additional measures in line with the “step-up approach” for managing severe AP[2,3,21-23].

DIAGNOSTIC AND THERAPEUTIC IMPLICATIONS OF ASCITES IN AP

The presence of ascites in AP although not pathognomonic carries substantial diagnostic and therapeutic implications. It serves as both a radiological and biochemical marker, aiding in the assessment of disease severity and informing clinical management strategies.

Diagnostic implications

From a diagnostic standpoint ascites is most commonly detected using CECT, which remains the imaging modality of choice in moderate to severe AP. The early identification of peritoneal fluid has been consistently associated with higher CT severity index scores, an increased risk of pancreatic necrosis, and a greater likelihood of persistent organ failure as reported in several studies[24-26]. Importantly, ascites may be visualized during the early interstitial phase of AP, offering prognostic insights before the full clinical picture develops.

Although routine analysis of ascitic fluid is not indicated in all patients, diagnostic paracentesis may be valuable in selected cases especially when infection, hemorrhage, or alternative intra-abdominal pathology is suspected. Biochemical analysis of pancreatic ascites typically reveals elevated amylase and lipase levels, consistent with pancreatic origin. Increased protein concentration and elevated inflammatory mediators such as IL-6 and TNF-α may further reflect the intensity of systemic inflammation[1-3,27,28]. In rare cases ascitic fluid analysis can help differentiate pancreatic ascites from other etiologies, such as cirrhosis or malignancy, especially in patients with overlapping conditions. Moreover, the emergence of ascites in the context of clinical deterioration or signs of abdominal compartment syndrome (ACS) should prompt urgent re-evaluation, including advanced imaging, surgical consultation, and intensified hemodynamic monitoring[18-20].

Therapeutic implications

While the management of ascites in AP is primarily supportive, its identification can significantly influence the therapeutic approach. Standard care includes aggressive intravenous fluid resuscitation, nutritional support, and close monitoring of organ function. However, in patients with massive ascites, refractory intra-abdominal hypertension, or evidence of secondary infection, therapeutic paracentesis or image-guided percutaneous catheter drainage may be warranted[2,3].

Such interventions can relieve elevated intra-abdominal pressure, improve respiratory mechanics, and reduce the risk of developing ACS. Additionally, serial drainage of enzyme-rich ascitic fluid may help mitigate the peritoneal inflammatory response although robust data from randomized studies remain limited[2,3,19]. In specific cases involving pancreatic duct disruption such as pancreatic ascites secondary to necrosis-related leakage endoscopic retrograde cholangiopancreatography with pancreatic duct stenting may be beneficial in controlling the source of leakage[16,18].

Moreover, based on our experience, we believe that early diagnostic paracentesis should be considered more frequently in patients with moderate to severe AP and significant ascites rather than being reserved for cases where infection is already suspected. This proactive approach can yield early biomarker data [e.g., lactate dehydrogenase (LDH), IL-6] that may signal impending deterioration and allow for pre-emptive escalation of care within a step-up approach.

Ultimately, the detection of ascites in the context of AP should prompt increased clinical vigilance, more frequent reassessment of intravascular volume status, and where necessary early multidisciplinary intervention. Timely recognition and appropriate management of ascites may not only aid in early risk stratification but also improve outcomes in patients with severe forms of AP (Figure 1).

ABDOMINAL PARACENTESIS: A BRIDGE BETWEEN DIAGNOSIS AND INTERVENTION IN ASCITIC AP

Abdominal paracentesis occupies an important role in the multidisciplinary management of AP complicated by ascites, offering both diagnostic clarity and therapeutic benefit. While not routinely performed in all cases, its selective use (particularly in patients with tense ascites, clinical signs of intra-abdominal hypertension, or ACS) can significantly influence decision-making and improve clinical outcomes[2,29-31].

Diagnostic utility

In patients with new-onset or worsening ascites during the course of AP, paracentesis enables differentiation between sterile inflammatory effusions, infected ascitic collections, hemorrhagic fluid, and pancreatic ductal leaks each associated with specific prognostic and therapeutic implications. Biochemical analysis of the ascitic fluid often reveals elevated amylase levels, high protein content, and neutrophilic predominance in the context of pancreatic leaks or enzymatic peritonitis, which typically respond to conservative management. In contrast, the detection of bacteria on Gram stain or positive ascitic fluid cultures indicates secondary infection, necessitating the initiation of targeted antibiotic therapy and possibly additional interventional or surgical procedures[1-3,29].

Therapeutic role

Beyond its diagnostic value paracentesis may serve as an initial therapeutic maneuver. Drainage of even a moderate volume of ascitic fluid can relieve intra-abdominal pressure, restore perfusion to vital organs, and improve respiratory parameters often producing immediate though temporary clinical improvement. This is particularly important in patients who are hemodynamically unstable and at risk of developing ACS[2,3,17,18,29].

Serial or repeated paracenteses can assist in monitoring disease progression and the effectiveness of conservative therapy. Persistent high-volume, enzyme-rich ascitic output or the emergence of encapsulated collections with enhancing walls may indicate the evolution toward walled-off pancreatic necrosis (WOPN), (formerly referred to as pancreatic abscess) or infected PPC. Such findings often prompt escalation to image-guided percutaneous catheter drainage or other definitive interventions. Thus, paracentesis functions as a diagnostic-therapeutic bridge within a step-up strategy, allowing for escalation of care only when clinically indicated, thereby avoiding unnecessary or premature procedures[32-36].

Safety and practical considerations

When performed under ultrasound guidance, abdominal paracentesis is generally safe, minimally invasive, and cost-effective. Nonetheless, potential complications such as hemorrhage, secondary infection, or bowel injury underline the importance of proper technique, anatomical knowledge, and judicious patient selection[2].

In the context of AP with ascites, abdominal paracentesis emerges as a valuable tool that bridges diagnosis and intervention. It facilitates early biochemical and microbiological assessment, provides therapeutic decompression, and serves as a gateway to timely escalation within a step-up management framework. When applied selectively and appropriately, paracentesis may reduce morbidity and contribute to improved clinical outcomes.

RELATIONSHIP BETWEEN PANCREATIC ASCITES AND THE FORMATION OF PPC OR WOPN

Pancreatic ascites arises from the leakage of pancreatic enzymes into the peritoneal cavity, most commonly due to disruption of the main pancreatic duct or its side branches or rupture of a peripancreatic fluid collection. Although relatively uncommon, it is a clinically significant manifestation of severe AP and is closely associated with the formation of PPC or WOPN, especially in the later stages of the disease.

The transition from enzyme-rich ascitic fluid to PPC formation follows a pathophysiological sequence involving persistent leakage of active pancreatic enzymes, primarily amylase and lipase, into the retroperitoneal or peritoneal space. This leakage results from ductal injury or necrosis and if not spontaneously resolved or externally drained may trigger the body’s attempt to contain the fluid through the development of a fibrous capsule, leading to PPC or WOPN formation after approximately 4 weeks[32-35,37].

Clinically, ongoing or recurrent pancreatic ascites is a strong predictor of PPC formation, especially in patients with disconnected pancreatic duct syndrome or confirmed main pancreatic duct disruption. Imaging modalities such as magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography are instrumental in identifying the site and extent of ductal disruption and visualizing communication between the ductal system and the peritoneal cavity[18,32-34].

Several studies have demonstrated that patients with pancreatic ascites have a heightened risk of developing large and symptomatic PPC, many of which require interventional management. The likelihood of PPC or WOPN formation correlates with both the volume and persistence of ascitic fluid, especially in cases with unresolved inflammation or inadequately managed ductal injury during the early stages of the disease[2,18,33-35].

From a clinical management perspective, the early identification of pancreatic ascites should prompt detailed evaluation for possible ductal disruption and close radiological monitoring, especially beyond the third or fourth week of illness. Timely intervention ranging from conservative management to endoscopic stenting may prevent the progression from free enzyme leakage to encapsulated PPC formation[4,18].

ASCITES IN AP: FROM PASSIVE EFFUSION TO PROGNOSTIC BIOMARKER

Ascitic fluid is frequently encountered in patients with moderate to severe AP. Once considered a passive byproduct of pancreatic enzyme leakage, vascular hyperpermeability, and peritoneal irritation, ascites is now increasingly recognized as both a marker and a potential driver of disease progression and systemic deterioration[2,3,38-40]. Its formation is primarily due to enzyme-rich leakage from inflamed or necrotic pancreatic tissue, accompanied by widespread inflammatory activation.

The volume and biochemical composition of ascitic fluid may reflect the extent of inflammation, particularly in necrotizing AP or cases involving pancreatic ductal disruption[11,13,18,40,41]. While elevated pancreatic enzymes are a hallmark of pancreatic ascites, their diagnostic value extends beyond enzymatic activity. Paracentesis provides access to ascitic fluid, allowing assessment of diverse cellular and biochemical markers that inform disease severity, infectious status, and clinical course.

Several ascitic parameters have been linked with poor outcomes in AP. Elevated neutrophil counts and high LDH levels indicate intense systemic inflammation, correlate with organ dysfunction, and are often associated with prolonged hospitalization. Similarly, early radiological detection of ascites (within 72 h of symptom onset) correlates with persistent organ failure, intensive care unit admission, and increased mortality, independent of traditional severity scores[1,23-25].

Among biochemical markers LDH remains the most widely utilized. As a cytosolic enzyme released during cell injury, it reflects ongoing tissue damage, inflammation, and microvascular compromise. In AP elevated ascitic LDH has been associated with pancreatic necrosis, systemic inflammatory response syndrome, multiorgan dysfunction, and extended hospitalization[2,42-45]. Its broad availability, low cost, and rapid turnaround make it particularly valuable for early risk stratification and escalation of care. Moreover, LDH may help distinguish between sterile and infected ascites an important clinical distinction guiding antimicrobial therapy and invasive interventions. When interpreted alongside findings such as neutrophilic predominance or low glucose levels, elevated LDH may suggest infection or peritonitis-like evolution, especially in patients exhibiting sepsis[18,45-47].

Despite its practicality, LDH is not among the most specific biomarkers for complications in AP-associated ascites. Proinflammatory cytokines such as IL-6 and TNF-α provide greater specificity for predicting infected necrosis and organ failure, but their clinical adoption is limited by cost, longer turnaround times, and restricted availability. Recent studies suggest that combining markers (for example, LDH with neutrophil count or IL-6) may further enhance prognostic accuracy compared with any single parameter. Thus, while LDH remains the most feasible biomarker in routine practice, cytokine-based assays may provide incremental value in selected patients or specialized centers[42-45,48-50]. Selected ascitic fluid parameters with potential diagnostic and prognostic value in AP are summarized in Figure 2.

Key ascitic fluid parameters with recognized diagnostic and prognostic utility (1) Bacterial cultures/PCR. Critical for detecting superinfection or infected necrosis; (2) Proinflammatory cytokines (e.g., IL-6, TNF-α). Emerging biomarkers for disease severity and systemic involvement; (3) Neutrophil count. Reflects the degree of local and systemic inflammation; (4) LDH. Distinguishes between sterile and infected ascites; (5) Glucose. Decreased levels may suggest infection or immune activation; (6) Potential of hydrogen. Acidosis may indicate infection or severe inflammation; (7) Amylase/Lipase. Indicative of pancreatic duct leakage or fistula; (8) Total protein and albumin. Characterize fluid as exudative and indicate vascular permeability; (9) Serum. Ascites albumin gradient-differentiates portal hypertension from pancreatic ascites; and (10) Cytology. Assists in excluding malignancy or detecting reactive changes. When interpreted in context and combined with early imaging (particularly CECT within 72 h) these parameters can significantly improve risk stratification, support prompt therapeutic decisions, and reduce delays in care[1,18-20,50].

A major unresolved gap in the current literature is the lack of large, prospective studies that establish and validate threshold values for ascitic fluid biomarkers (e.g., LDH, IL-6) in predicting clinically relevant outcomes such as infected necrosis or organ failure. Future investigations should prioritize the determination of these cutoff points and their integration into multimodal prognostic models to improve risk stratification and guide evidence-based clinical decision-making.

In addition, evidence from clinical practice suggests that the ascitic fluid LDH-to-serum amylase ratio, a simple and readily obtainable parameter, warrants systematic evaluation due to its potential to differentiate sterile from infected collections at an earlier stage than conventional clinical signs. The timely recognition of such prognostic indicators could refine diagnostic accuracy and facilitate earlier therapeutic interventions, thereby improving patient outcomes.

Beyond their diagnostic role, large or persistent ascitic collections may actively worsen outcomes by raising intra-abdominal pressure, contributing to ACS, and impairing both perfusion and ventilation[18-20,48]. Serial imaging studies have shown that unresolved ascites often precedes complications such as infected necrosis, PPC, or persistent ductal leakage[2,36,37,51,52].

Altogether, these observations reinforce that ascitic fluid in AP is not merely a passive effusion but a dynamic and pathophysiologically active component of disease progression. Easily accessible markers such as LDH provide practical value in early prognostication while advanced biomarkers including cytokines and molecular diagnostics may enhance specificity and therapeutic precision. Incorporating ascitic fluid analysis into routine clinical evaluation may substantially improve the accuracy and timeliness of AP management.

CONCLUSION

Ascitic fluid in AP should be regarded not only as a byproduct of pancreatic injury but also as a clinically meaningful indicator of disease severity. Its presence warrants heightened clinical vigilance, timely reassessment, and when indicated escalation of care. Future prospective studies are essential to validate the prognostic accuracy of ascitic fluid biomarkers, to establish clinically applicable cut-off values, and to integrate fluid analysis into multimodal prognostic frameworks. Importantly, such studies should also evaluate the prognostic relevance of ascites across different AP subtypes as pathophysiological mechanisms and fluid characteristics may vary by etiology. A clear research agenda should include large multicenter trials, development of a standardized ascitic fluid risk score, and systematic evaluation of early, protocol-driven paracentesis to guide fluid management and antibiotic use. Although ascitic fluid analysis is not yet routine, its potential to enhance early prognostication and support personalized management in AP is substantial, warranting inclusion in future research protocols and guidelines.