Biomarkers in Acute Pancreatitis: Integrating Current Evidence with Pathophysiology and Clinical Practice.

Acute pancreatitis (AP) is an inflammatory condition characterized by the sudden onset of pancreatic injury and a wide spectrum of clinical severity. Although most patients experience mild disease with spontaneous recovery, approximately 20%–30% develop moderate to severe AP associated with pancreatic necrosis, systemic inflammatory response syndrome (SIRS), multiorgan failure, and mortality rates approaching 30% in severe cases.[] AP is among the most common causes of gastrointestinal hospitalization worldwide, with rising incidence linked to gallstone disease, alcohol use, hypertriglyceridemia, obesity, and metabolic syndrome.[] Despite advances in supportive care and imaging, early identification of patients at risk for severe disease remains challenging. Clinical scoring systems such as Ranson’s criteria, APACHE II, and BISAP provide prognostic information but are limited by complexity, delayed applicability, and modest accuracy.[] Radiologic imaging, particularly contrast-enhanced computed tomography, offers valuable structural assessment but may not detect early inflammatory changes or predict disease progression during the initial phase. Biomarkers have therefore emerged as essential adjuncts in the diagnosis and management of AP. They offer rapid, objective, and reproducible measurements that reflect pancreatic injury, inflammatory burden, immune activation, and infectious complications. While classical enzymatic biomarkers such as serum amylase and lipase remain cornerstones of diagnosis, their inability to predict severity or outcomes has prompted extensive investigation into inflammatory cytokines, acute-phase proteins, and molecular activation markers.[] The purpose of this review is to provide a comprehensive evaluation of established and emerging biomarkers in AP. By integrating pathophysiological mechanisms with clinical evidence, this article aims to clarify the diagnostic and prognostic value of biomarkers, discuss their limitations, and highlight future directions toward biomarker-driven personalized management. PATHOPHYSIOLOGICAL BASIS FOR BIOMARKERS OF ACUTE PANCREATITIS The pathogenesis of AP is initiated by injury to pancreatic acinar cells, resulting in premature intracellular activation of digestive enzymes, particularly the conversion of trypsinogen to trypsin. This aberrant enzyme activation leads to pancreatic autodigestion, acinar cell necrosis, and local inflammatory injury.[] Local tissue damage rapidly activates the innate immune system. Resident macrophages and recruited neutrophils release pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α (TNF-α), amplifying pancreatic injury and promoting systemic inflammation.[] Concurrent endothelial activation increases vascular permeability, contributing to pancreatic edema, impaired microcirculation, and ischemic injury. In severe cases, inflammatory mediators disseminate into the systemic circulation, triggering SIRS and distant organ dysfunction, most commonly affecting the lungs, kidneys, and cardiovascular system. The balance between pro-inflammatory and anti-inflammatory mediators, particularly IL-10, is a critical determinant of disease severity and outcome.[] Persistent immune dysregulation may lead to immunosuppression, predisposing patients to secondary infections and infected pancreatic necrosis. Biomarkers reflect different components of this evolving pathophysiological cascade. Enzymatic biomarkers indicate acinar cell damage, acute-phase reactants reflect systemic inflammation, cytokines mirror immune activation, and infection-related biomarkers signal septic complications.[] Understanding these mechanisms is essential for appropriate biomarker interpretation and clinical application. BIOMARKERS IN ACUTE PANCREATITIS Biomarkers in AP represent measurable biological indicators that reflect pancreatic injury, inflammatory activation, immune dysregulation, and infectious complications. Because AP is a dynamic disease with distinct early and late phases, biomarkers differ in their temporal expression and clinical significance. An ideal biomarker should allow early diagnosis, accurately predict disease severity, identify complications such as infected necrosis, and guide clinical decision-making. However, no single biomarker fulfills all these criteria, necessitating a multimodal approach. ENZYMATIC BIOMARKERS OF PANCREATIC INJURY Serum amylase Serum amylase is an enzyme secreted by pancreatic acinar cells and salivary glands. In AP, acinar cell injury and ductal disruption lead to leakage of amylase into the circulation, with serum levels typically rising within 6–12 h of symptom onset and peaking within 24 h. Traditionally, a threefold increase above the upper limit of normal has been used as a diagnostic criterion.[] Despite its historical importance, serum amylase has several limitations. Its specificity is poor, as elevated levels may occur in salivary gland inflammation, bowel obstruction, ischemia, perforation, renal failure, and gynecologic conditions. Furthermore, amylase levels decline rapidly and may normalize within 3–5 days, even in patients with ongoing pancreatic inflammation. Importantly, serum amylase shows poor correlation with disease severity, pancreatic necrosis, or clinical outcomes.[] In alcohol-related pancreatitis and hypertriglyceridemia-induced pancreatitis, serum amylase may be only mildly elevated or normal, further limiting its diagnostic sensitivity. Consequently, serum amylase is no longer recommended as a standalone diagnostic or prognostic biomarker but may still be used in conjunction with lipase in selected settings. Serum lipase Serum lipase has largely replaced amylase as the preferred enzymatic biomarker for diagnosing AP. Lipase is more pancreas-specific and remains elevated longer, typically for 8–14 days, enhancing diagnostic sensitivity in delayed presentations.[] Lipase rises within 4–8 h of symptom onset and peaks at approximately 24 h. Compared with amylase, lipase is less affected by nonpancreatic conditions and provides greater diagnostic accuracy. However, similar to amylase, serum lipase levels do not correlate with the severity of pancreatic inflammation, extent of necrosis, or risk of organ failure.[] Thus, while serum lipase is indispensable for confirming the diagnosis of AP, it does not provide meaningful prognostic information and should not be used to guide severity-based management decisions. ACUTE-PHASE PROTEINS AND SYSTEMIC INFLAMMATORY BIOMARKERS C-reactive protein C-reactive protein (CRP) is an acute-phase reactant synthesized by hepatocytes in response to inflammatory cytokines, particularly IL-6. In AP, CRP reflects the magnitude of systemic inflammation rather than direct pancreatic injury. CRP levels begin to rise within 12–24 h of symptom onset and peak at approximately 48 h.[] Numerous studies have demonstrated that CRP levels exceeding 150 mg/L are strongly associated with severe AP, pancreatic necrosis, prolonged hospitalization, and increased mortality. Because of its low cost, wide availability, and reproducibility, CRP remains the most widely used prognostic biomarker in routine clinical practice.[] However, CRP has notable limitations. Its delayed peak reduces utility in very early severity prediction, and elevated levels may be influenced by concomitant infections, trauma, or chronic inflammatory diseases. Despite these limitations, CRP remains a cornerstone biomarker when interpreted alongside clinical findings and imaging. White blood cell count and derived indices Leukocytosis is a common laboratory finding in AP and reflects systemic inflammatory activation. More recently, derived hematologic indices such as the neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio have been investigated as severity predictors. Elevated neutrophil-to-lymphocyte ratio has been associated with increased risk of severe disease, organ failure, and mortality.[] These indices offer the advantages of low cost and universal availability. However, they lack specificity and are influenced by stress responses, infection, and comorbid conditions. As such, they should be used as adjunctive markers rather than standalone predictors. CYTOKINES AND IMMUNE RESPONSE BIOMARKERS Interleukin-6 IL-6 is a central mediator of the inflammatory response and a key regulator of hepatic acute-phase protein synthesis. In AP, IL-6 levels rise rapidly, often within the first 24 h, preceding CRP elevation. Elevated IL-6 levels correlate strongly with disease severity, development of organ failure, and mortality.[] Several comparative studies have demonstrated that IL-6 outperforms CRP and traditional clinical scoring systems in early severity prediction. However, routine clinical use of IL-6 is limited by assay cost, lack of standardization, and limited availability in many healthcare settings. Interleukin-8 and tumor necrosis factor-α IL-8 plays a critical role in neutrophil recruitment and activation and has been associated with pancreatic necrosis and pulmonary complications. TNF-α contributes to endothelial dysfunction, microvascular injury, and SIRS.[] Although these cytokines provide valuable insight into disease pathogenesis, their short half-lives, significant interindividual variability, and assay limitations restrict routine clinical use. Interleukin-10 IL-10 is an anti-inflammatory cytokine that counterbalances pro-inflammatory responses. Lower IL-10 levels in early disease have been associated with severe AP, reflecting inadequate immune regulation. Combined assessment of pro- and anti-inflammatory cytokines may enhance prognostic accuracy, though clinical application remains limited.[] PROCALCITONIN AND INFECTION-RELATED BIOMARKERS Procalcitonin (PCT) is a prohormone that increases markedly in response to bacterial infection and systemic inflammation. In AP, elevated PCT levels are strongly associated with infected pancreatic necrosis, sepsis, and multiorgan failure.[] Compared with CRP, PCT demonstrates superior specificity for infectious complications and may guide antibiotic stewardship. Persistently elevated or rising PCT levels are indicative of poor prognosis and warrant aggressive monitoring or escalation of care.[] MARKERS OF ENZYME ACTIVATION AND PANCREATIC NECROSIS Trypsinogen activation peptides Trypsinogen activation peptides (TAPs) reflect premature intrapancreatic activation of trypsinogen, the central event in AP pathogenesis. Elevated levels correlate with disease severity, pancreatic necrosis, and systemic complications.[] Despite excellent diagnostic and prognostic performance, clinical use is limited by a lack of standardized assays and availability. OTHER ENZYME-RELATED BIOMARKERS Pancreatic elastase and phospholipase A2 have been studied as markers of pancreatic necrosis and severity. Although promising, inconsistent results and technical challenges have limited their adoption into routine practice. NOVEL AND EMERGING MOLECULAR BIOMARKERS Advances in molecular biology and high-throughput analytical technologies have expanded the understanding of AP beyond conventional enzymatic and inflammatory markers. Novel and emerging molecular biomarkers provide mechanistic insights into acinar cell injury, immune activation, endothelial dysfunction, and metabolic stress, which are central to disease progression. Unlike traditional biomarkers that reflect downstream inflammation, these markers are often involved in upstream pathogenic pathways and may therefore enable earlier prediction of disease severity and clinical outcomes.[,] Pentraxin-3 Pentraxin-3 (PTX3) is a long pentraxin produced locally at sites of inflammation by endothelial cells, macrophages, and dendritic cells, in contrast to CRP, which is synthesized primarily in the liver. In AP, PTX3 is rapidly released in response to tissue injury and innate immune activation, reflecting localized inflammation and microvascular damage. Elevated PTX3 levels have been shown to correlate with severe AP, pancreatic necrosis, organ failure, and increased mortality, often outperforming traditional acute-phase reactants in early disease stages.[] Because microcirculatory dysfunction and endothelial injury are key determinants of pancreatic necrosis and systemic complications, PTX3 may serve as a more direct indicator of disease severity. Although its clinical application is currently limited by assay availability and cost, PTX3 represents a promising biomarker for early risk stratification in AP.[] Pentaxin 3 is a molecule involved in the immune response during inflammation and cancer progression. Unlike CRP, PTX3 can act as a swift indicator of the activation of primary local innate immunity and inflammatory states. The relationship between PTX3 concentration and the severity of these processes remains unclear. It is hypothesized that elevated levels of PTX3 may be associated with a worse prognosis in malignancies, such as pancreatic cancer.[] Under typical physiological circumstances, plasma PTX3 concentrations are minimal (<2 ng/mL in humans); however, they escalate swiftly during inflammatory conditions, attaining levels between 100 and 1000 ng/mL, contingent upon the severity of the disease.[] One of the primary benefits of PTX3 as a biomarker is its swift kinetics. PTX3 concentrations increase within 6–8 h following inflammatory stimulation, reaching their peak sooner than CRP, and exhibit a strong correlation with disease severity, pancreatic necrosis, and the likelihood of complications. Research has shown that PTX3 levels are markedly elevated in patients suffering from severe AP in comparison to those with mild cases, thereby establishing it as a crucial early indicator of severity.[] MicroRNAs MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression at the posttranscriptional level and play crucial roles in inflammatory signaling, apoptosis, and cellular stress responses. In AP, dysregulated expression of specific miRNAs has been linked to acinar cell injury, cytokine production, and progression to SIRS. Several circulating miRNAs, including pancreas-specific and inflammation-associated subtypes, have demonstrated associations with disease severity, pancreatic necrosis, and persistent organ failure.[] One of the key mechanisms involved in the pathophysiology of AP is the activation of inflammatory signaling pathways, with a particular emphasis on the nuclear factor-kappa B (NF-κB) pathway. Various miRNAs, including miR-21, miR-155, and miR-146a, are recognized for their role in modulating NF-κB signaling. For example, miR-155 facilitates inflammation by increasing the production of pro-inflammatory cytokines such as TNF-α and IL-6, while miR-146a functions as a negative feedback regulator, reducing excessive inflammation.[,] The dysregulation of these miRNAs leads to an amplified inflammatory response, resulting in damage to pancreatic tissue and the development of SIRS.[] Besides their local effects on the pancreas, miRNAs also play a role in the systemic complications associated with AP. These circulating miRNAs enter the bloodstream either through passive leakage from injured cells or through active secretion via exosomes and microvesicles. Once in circulation, these miRNAs can function as intercellular signaling molecules, influencing immune responses in remote organs, including the lungs, kidneys, and liver. This process is especially significant in the onset of multiple organ dysfunction syndrome.[] One of the major advantages of miRNAs as biomarkers is their stability in serum and plasma, resistance to enzymatic degradation, and disease-specific expression patterns. Early studies suggest that miRNA profiling may allow discrimination between mild and severe AP earlier than conventional biomarkers such as CRP. However, lack of assay standardization, interstudy variability, and limited clinical availability currently restrict their routine use.[] PROTEOMIC AND METABOLOMIC BIOMARKERS Proteomic and metabolomic analyses have provided a systems-level perspective on the molecular alterations associated with AP. Proteomic studies have identified changes in proteins involved in complement activation, coagulation pathways, oxidative stress, and extracellular matrix remodeling, all of which contribute to disease severity and organ dysfunction. Similarly, metabolomic profiling has revealed alterations in amino acid metabolism, lipid signaling pathways, and energy homeostasis, reflecting mitochondrial dysfunction and systemic metabolic stress during severe disease.[] These omics-based approaches offer the advantage of capturing complex molecular interactions rather than isolated biomarkers. Combined proteomic and metabolomic signatures have demonstrated potential for differentiating mild from severe AP and for predicting complications such as multiorgan failure. Nevertheless, high cost, technical complexity, and the need for external validation currently limit their translation into routine clinical practice.[] GENETIC AND EPIGENETIC BIOMARKERS Genetic predisposition influences both susceptibility to AP and disease severity. Variants in genes involved in trypsin regulation, inflammatory signaling, and oxidative stress responses have been associated with increased risk of severe disease and recurrent pancreatitis. In addition, epigenetic mechanisms such as DNA methylation and histone modification modulate inflammatory gene expression during pancreatic injury and recovery.[,] Although genetic and epigenetic biomarkers are not currently used for acute severity assessment, they provide valuable insights into disease pathogenesis and long-term outcomes. Integration of genetic susceptibility markers with circulating inflammatory and molecular biomarkers may enhance personalized risk stratification in the future.[] EXTRACELLULAR VESICLES AND DAMAGE-ASSOCIATED MOLECULAR PATTERNS Extracellular vesicles, including exosomes, are released during cellular stress and injury and carry proteins, lipids, and nucleic acids reflective of their cellular origin. In AP, extracellular vesicles derived from injured acinar cells and activated immune cells have been implicated in the propagation of systemic inflammation and distant organ injury. In parallel, damage-associated molecular patterns released from necrotic pancreatic tissue activate innate immune receptors and amplify inflammatory signaling cascades.[,] Although these biomarkers remain largely experimental, they represent an emerging area of research with potential implications for early diagnosis, severity prediction, and therapeutic targeting in AP.[] CLINICAL IMPLICATIONS AND FUTURE DIRECTIONS Emerging molecular biomarkers represent a shift toward precision medicine in AP by enabling earlier and more accurate assessment of disease severity and progression. While most remain confined to research settings, continued technological advances, assay standardization, and validation studies are likely to facilitate their clinical translation. Future biomarker strategies will likely involve multimarker panels that integrate molecular, inflammatory, and clinical parameters to optimize early decision-making and individualized patient management.[,] BIOMARKER PANELS AND INTEGRATED APPROACHES Table 1 shows conceptual link between pathophysiology and biomarkers. No single biomarker captures the complexity of AP. Multimarker panels and integration with clinical scoring systems improve predictive accuracy. Machine learning–based models incorporating biomarkers show promise for early risk stratification.[] The development of AP can be categorized into three distinct phases: Early, intermediate, and late, each defined by unique pathophysiological changes and specific biomarkers. During the early phase, the activation of enzymes in pancreatic acinar cells is the predominant event. Biomarkers such as TAP and carboxypeptidase activation peptide increase significantly, often within hours of the onset of symptoms, indicating direct injury to the pancreas. Concurrently, miRNAs (for instance, miR-216a and miR-375) are released into the bloodstream as a result of cellular stress and damage, acting as highly sensitive early markers.[] During the intermediate phase, the inflammatory cascade becomes predominant. Pro-inflammatory cytokines, including IL-6 and TNF-α, enhance immune responses, whereas biomarkers such as PCT signify systemic inflammation and potential infection. Acute-phase proteins, notably PTX3 and serum amyloid A, represent both local and systemic inflammatory burdens, thereby connecting pancreatic injury with the systemic response.[] In the late phase, complications arise, including pancreatic necrosis, secondary infections, and organ dysfunction. Biomarkers such as high-mobility group box 1 indicate necrotic cell death and ongoing inflammation, while endothelial markers like angiopoietin-2 and adhesion molecules like Intercellular Adhesion Molecule-1 (ICAM-1 and VCAM-1) signify vascular injury and microcirculatory failure.[] Clinical Utility and Limitations Biomarkers offer an objective assessment but are influenced by timing, comorbidities, assay variability, and cost. Lack of standardized cutoff values and limited availability of novel assays remain barriers to widespread adoption.[] Emerging biomarkers in AP have enhanced the objective assessment of disease activity by providing early insight into inflammatory, immunological, and necrotic pathways involved in disease progression. Biomarkers such as interleukins, PCT, PTX3, and circulating miRNAs reflect key components of systemic inflammation, immune activation, and infection, thereby enabling earlier identification of patients at risk for severe disease and complications. Their early rise during the disease course supports timely risk stratification and may assist clinicians in making decisions regarding intensive monitoring, escalation of care, and targeted therapeutic interventions. In particular, PCT has demonstrated clinical value in identifying infected pancreatic necrosis and guiding appropriate antibiotic use.[,] Despite these advantages, several limitations restrict their widespread clinical application. Biomarker levels exhibit significant temporal variation, and their diagnostic or prognostic accuracy depends on the timing of measurement during the disease course. In addition, their concentrations may be influenced by coexisting conditions such as systemic infections, chronic inflammatory diseases, renal impairment, and metabolic disturbances, thereby reducing specificity. Variability in assay methodologies and lack of standardization across laboratories further complicate the interpretation of results. Another major limitation is the absence of universally accepted cutoff values for most novel biomarkers, which hinders their incorporation into routine clinical decision-making. Economic considerations and limited availability of advanced assays, particularly in resource-limited settings, also pose challenges. Furthermore, many emerging biomarkers require validation through large-scale prospective studies before being integrated into established clinical guidelines. Therefore, at present, the optimal use of novel biomarkers lies in combination with clinical assessment and established scoring systems rather than as standalone tools.[,]

AP remains a heterogeneous disease with unpredictable progression. While traditional enzymatic biomarkers remain essential for diagnosis, inflammatory and molecular biomarkers provide critical prognostic information. Understanding the pathophysiological basis of biomarker release enables rational clinical application. Emerging biomarkers and multimodal approaches hold promise for personalized management, improved outcomes, and optimized resource utilization. New biomarkers collectively illustrate this continuum, offering a thorough depiction of disease initiation, advancement, intensity, and results. A unified biomarker strategy acknowledges that each marker is associated with a distinct phase of the disease process, while also exhibiting considerable overlap with others, thereby creating a synchronized biological network. Future research should focus on validation, standardization, and integration of biomarkers into predictive clinical frameworks. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgment We would like to thank our colleagues at the Department of Biochemistry, Smt. B.K.Shah Medical Institute and Research Centre, Sumandeep Vidyapeeth, Piparia, Vadodara, Gujarat.

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