Acute pancreatitis pathophysiology

Jump to navigation Jump to search

Acute pancreatitis Microchapters

Home

American College of Gastroenterology Guidelines

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Acute Pancreatitis from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

Diagnostic criteria

History and Symptoms

Physical Examination

Laboratory Findings

Abdominal X Ray

CT

MRI

Ultrasound

Other Imaging Findings

Other Diagnostic Studies

Treatment

Approach to Therapy

Medical Therapy

Surgery

Primary Prevention

Secondary Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Acute pancreatitis pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Acute pancreatitis pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Acute pancreatitis pathophysiology

CDC on Acute pancreatitis pathophysiology

Acute pancreatitis pathophysiology in the news

Blogs on Acute pancreatitis pathophysiology

Directions to Hospitals Treating Acute pancreatitis

Risk calculators and risk factors for Acute pancreatitis pathophysiology 

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[2]

Pathophysiology

This section covers the cellular, molecular, and systemic mechanisms underlying acute pancreatitis (AP), focusing on pathways that directly inform clinical understanding of disease severity, prognosis, and therapeutic targets. Content spans acinar, ductal, and stellate cell injury, calcium-mitochondrial dysfunction, cell death pathways, impaired autophagy, lipotoxicity, the inflammatory cascade from local to systemic disease, gut barrier dysfunction, intra-abdominal hypertension, and the biphasic model of organ failure. Etiology-specific mechanisms (gallstone, alcohol, hypertriglyceridemia, drug-induced, post-ERCP) are addressed only to the extent that they illuminate distinct pathophysiologic pathways. Genetic susceptibility mechanisms are summarized briefly; detailed etiologic listings, clinical management, and investigational therapeutics are deferred to their respective microchapters.

Acinar Cell Injury and Premature Trypsinogen Activation

The pancreatic acinar cell is the primary site of initial injury in AP. Under physiologic conditions, digestive enzymes are synthesized, stored as inactive zymogens in zymogen granules, and secreted into the duodenum where enterokinase activates trypsinogen to trypsin, which in turn activates other zymogens.[1][2] Multiple protective mechanisms prevent intrapancreatic trypsin activity: compartmentalization of zymogens, synthesis of the specific trypsin inhibitor SPINK1, autolysis of prematurely activated trypsin, and maintenance of low intracellular ionized calcium concentrations.

In AP, these safeguards are overwhelmed. The initiating event involves co-localization of lysosomal hydrolases (particularly cathepsin B) with zymogen granules within acinar cells, leading to premature intrapancreatic trypsinogen activation.[3][4] Cathepsin B cleaves trypsinogen to trypsin, which then activates additional zymogens (elastase, phospholipase A2, chymotrypsinogen) and triggers the complement and kinin cascades, resulting in autodigestion of pancreatic parenchyma. Recent biochemical work has identified cystatin C (CST3) as a critical endogenous regulator of cathepsin B and cathepsin L activity; trypsin can cleave CST3, converting it from an inhibitor to an activator of cathepsin B, thereby creating a positive feedback loop that amplifies the intrapancreatic protease cascade.

However, the traditional "trypsin-centric" theory has been substantially refined. Genetic mouse models in which trypsinogen activation is eliminated (T7D23A knock-in mice) still develop significant pancreatitis responses, including acinar cell death and inflammation.[5] Current evidence suggests that trypsin is a mediator rather than the sole driver of disease, and that other intra-acinar pathologic processes — particularly defective autophagy, mitochondrial dysfunction, and calcium toxicity — play equally or more critical roles in disease initiation and progression, though whether trypsin-independent mechanisms are sufficient on their own in human (rather than murine) disease remains an open question.


In AP, pancreatitis-inducing toxins (bile acids, fatty acid ethyl esters [FAEEs], supramaximal cholecystokinin stimulation) cause a sustained, global elevation of cytosolic Ca2+ through several mechanisms:[6][7]

  • Excessive Ca2+ release from ER stores via IP3 and ryanodine receptors
  • Sustained store-operated Ca2+ entry (SOCE) through plasma membrane ORAI1 channels regulated by STIM1/2
  • Impaired Ca2+ clearance due to ATP depletion affecting SERCA (ER reuptake) and PMCA (plasma membrane extrusion) pumps

Pathologic Ca2+ signaling also activates the phosphatase calcineurin, which mediates both premature trypsinogen activation and NF-κB activation. Bile acids activate calcineurin to injure acinar cells, transient high pancreatic ductal pressure promotes inflammation and disrupts tight junctions via calcineurin signaling, and pharmacologic or genetic calcineurin inhibition reduces pancreatitis severity in multiple experimental models, with the protective effect dependent on the pancreatic acinar cell source of calcineurin rather than hematopoietic cells.[8][9][10][11]

This Ca2+ overload has multiple downstream consequences: premature trypsinogen activation, mitochondrial Ca2+ overload via the mitochondrial calcium uniporter (MCU), opening of the mitochondrial permeability transition pore (MPTP), and ultimately acinar cell necrosis. The vicious cycle of Ca2+ overload → mitochondrial failure → ATP depletion → further impairment of Ca2+ clearance is now recognized as a central pathogenic loop in AP.

Mitochondrial Dysfunction

Mitochondrial injury is increasingly recognized as a key early event that may precede both cytokine release and trypsinogen activation.[12] The principal manifestation is persistent opening of the MPTP, a cyclophilin D (CypD)-dependent solute channel, which causes:[13]

  • Loss of mitochondrial membrane potential (ΔΨm)
  • Mitochondrial fragmentation
  • Collapse of oxidative phosphorylation and ATP depletion
  • Release of mitochondrial contents (cytochrome c, mitochondrial DNA) into the cytosol

The mechanisms of MPTP opening are model-specific: Ca2+ overload drives MPTP opening in cerulein-induced pancreatitis, inhibition of ATP synthase mediates it in arginine-induced pancreatitis, and a decreased NAD+/NADH ratio from oxidative alcohol metabolism triggers it in alcohol-induced pancreatitis. Importantly, CypD genetic deletion or pharmacologic inhibition prevents mitochondrial depolarization and greatly reduces pancreatic, systemic, and pulmonary injury across all experimental models.

Released mitochondrial DNA acts as a damage-associated molecular pattern (DAMP), activating the cGAS-STING1 pathway, NF-κB signaling, and NLRP3 inflammasomes, thereby linking mitochondrial injury directly to the inflammatory cascade.[14]

Impaired Autophagy

Autophagy — the lysosomal degradation pathway for recycling damaged organelles and long-lived proteins — is characteristically impaired in AP. This impairment results from defective lysosomal function rather than insufficient autophagosome formation: lysosomal cathepsin processing is defective, lysosomal-associated membrane protein 2 (LAMP-2) levels are dramatically reduced, and vacuolar proton ATPase localization is altered, all leading to accumulation of large autolysosomes containing poorly degraded cargo.

The functional consequences of impaired autophagy are significant:

  • Accumulation of damaged mitochondria (failed mitophagy), perpetuating the mitochondrial dysfunction–ATP depletion cycle
  • Persistence of activated zymogens within vacuoles
  • ER stress through accumulation of misfolded proteins
  • Deregulated lipid metabolism in acinar cells

Genetic models confirm the essential role of autophagy: pancreas-specific knockout of ATG5 or ATG7 causes spontaneous pancreatitis with trypsinogen activation, inflammation, fibrosis, and acinar-to-ductal metaplasia. Conversely, enhancing autophagic flux with trehalose largely prevents trypsinogen activation and necrosis in experimental models, and normalizes the downstream consequences of mitochondrial dysfunction.[15]

Ductal Cell Injury and Impaired Bicarbonate Secretion

Although acinar cells have traditionally been the focus of AP pathogenesis, pancreatic ductal cells play a critical protective role through secretion of bicarbonate-rich fluid that maintains alkaline intraductal pH and washes out protein-rich acinar secretions. Pancreatitis-inducing agents (bile acids, ethanol, nonoxidative ethanol metabolites) cause sustained Ca2+ overload in ductal cells via apical Orai1 channels, impairing CFTR-mediated bicarbonate and fluid secretion. The resulting luminal acidification enhances pathologic trypsinogen activation. Mice with selectively impaired ductal function (NHERF-1 knockout, causing CFTR mislocalization) develop more severe pancreatitis despite normal acinar and immune cell function, providing direct evidence that ductal dysfunction amplifies disease severity.[16] This mechanism also explains the clinical association between CFTR mutations and recurrent AP.[17][18][19]

Stellate Cell Amplification Loop

Pancreatic stellate cells (PSCs) contribute to an intercellular amplification loop that promotes acinar cell necrosis. Trypsin and kallikrein released from dying acinar cells generate bradykinin, which activates B2 receptors on PSCs, inducing Ca2+ signals and nitric oxide production that further damages neighboring acinar cells. In alcohol-related AP, PSCs lose their normal bradykinin responsiveness but acquire sensitivity to trypsin via protease-activated receptors, creating a vicious circle of progressive necrosis. Inhibition of Ca2+ entry through CRAC channels in PSCs reduces acinar cell necrosis in experimental models, identifying this intercellular pathway as a potential therapeutic target.[20][21][22]


Lipotoxicity and Unsaturated Fatty Acids

Peripancreatic and visceral fat lipolysis by leaked pancreatic lipases generates unsaturated fatty acids (UFAs) — predominantly linoleic, oleic, and palmitoleic acid — that are enriched in human pancreatic necrotic collections (15–25% linoleic acid composition). These UFAs inhibit mitochondrial complexes I and V, cause acinar cell necrosis, induce ARDS-like lung injury, elevate BUN via renal tubular injury, and trigger DAMP-mediated cytokine release (TNF-α, IL-1β, MCP-1, IL-18). Critically, UFA-mediated lipotoxicity can convert mild AP to severe AP independent of pancreatic parenchymal necrosis, as demonstrated by the finding that lipase inhibition (orlistat) prevents fat necrosis, organ failure, and mortality without affecting AP induction parameters. In human cohorts, circulating UFA levels (particularly palmitoleic acid) independently correlate with severe AP. This pathway provides a mechanistic explanation for the well-established association between obesity (particularly visceral adiposity) and AP severity, and identifies lipase inhibition as a potential therapeutic target.[23][24][25][26]

Cell Death Pathways and Disease Severity

The mode of acinar cell death is a critical determinant of disease severity. Multiple regulated cell death (RCD) pathways operate in AP, and their relative balance shapes the clinical phenotype:[27][28]

  • Apoptosis (1–5% of acinar cells): inversely correlated with disease severity; represents a relatively "clean" death that does not provoke significant inflammation
  • Necroptosis (a major proportion of dying cells in murine cerulein models; the exact proportion in human AP is unknown): a regulated form of necrosis mediated by the RIP1/RIP3/MLKL necrosome complex, triggered by TNF, Fas ligand, and TLR signaling; releases DAMPs that activate NLRP3 inflammasomes
  • Pyroptosis: inflammasome-mediated inflammatory cell death downstream of DAMP signaling
  • Ferroptosis: lipid peroxidation-driven cell death, increasingly implicated in intestinal barrier injury during severe AP

The switch from apoptosis to necrosis is governed primarily by ATP availability and caspase function. When mitochondrial dysfunction depletes ATP, caspase-dependent apoptosis cannot proceed, and cells default to necrosis or necroptosis. Chronic ethanol exposure depletes LAMP-2, blocks autophagy, reduces caspase activation, and shifts cell death toward necrosis — accompanied by nuclear release of the pro-inflammatory DAMP HMGB1.[29] Interventions that shift the balance from necrosis toward apoptosis (e.g., XIAP inhibition, RIP3 deletion, necrostatin treatment) consistently reduce disease severity in experimental models.

Etiology-Specific Pathophysiologic Mechanisms

Gallstone pancreatitis results from transient obstruction of the pancreatic duct by migrating stones or sludge, causing increased ductal pressure, interstitial edema, and accumulation of enzyme-rich fluid, which triggers acinar cell injury and premature enzyme activation.

Regardless of the route of bile acid exposure, bile acids injure acinar cells through multiple signaling pathways. At sub-micellar concentrations, unconjugated bile acids activate the G-protein-coupled cell surface receptor Gpbar1 (TGR5), triggering pathologic Ca2+ transients via IP3 receptors; Gpbar1 deletion protects mice from bile acid-induced pancreatitis, suggesting biliary AP may be, at least in part, a receptor-mediated disease. Bile acids are also internalized via apical and basolateral bile acid transporters and exert injurious effects intracellularly through both IP3 and ryanodine receptor-mediated Ca2+ release from ER and acidic stores at the apical pole of acinar cells.[30][31] Conjugated bile acids acting via TGR5 on macrophages inhibit NLRP3 inflammasome activation through the cAMP-PKA axis (PKA phosphorylates NLRP3 at Ser291, promoting its ubiquitination), an anti-inflammatory counter-mechanism distinct from the pro-injury TGR5 signaling in acinar cells.[32][33]

Alcohol-induced pancreatitis involves both oxidative and nonoxidative metabolic pathways within acinar cells.[34] The oxidative pathway (via ADH and CYP2E1) produces acetaldehyde and ROS, depletes mitochondrial glutathione, and reduces the NAD+/NADH ratio, opening the MPTP. The nonoxidative pathway generates fatty acid ethyl esters (FAEEs), which accumulate in mitochondria, release fatty acids that cause Ca2+ overload via IP3 receptor activation, impair SERCA/PMCA pump function, and trigger the Ca2+–mitochondrial dysfunction–ATP depletion cycle.[35] FAEEs also disrupt lysosomal and zymogen granule membranes, impair autophagy, and activate NF-κB. Alcohol additionally induces ER stress through the unfolded protein response (UPR); the adaptive UPR may explain why only a minority of heavy drinkers develop clinical pancreatitis. Smoking synergistically exacerbates alcohol-induced ER stress and acinar cell death.

Hypertriglyceridemia-induced pancreatitis (typically at triglyceride levels >1000 mg/dL) involves pancreatic lipase-mediated hydrolysis of excess triglycerides both locally within the pancreatic microcirculation and systemically in the intravascular space, generating toxic nonesterified fatty acids (NEFAs) — predominantly long-chain unsaturated species — that cause acinar cell injury, capillary endothelial damage, and local oxidative stress. A prospective study of 269 AP patients found that patients with HTG-AP had higher serum NEFA levels and more severe disease (19% vs. 7% severe AP), and that NEFA-TGFA × lipase correlations strengthened above a triglyceride level of 500 mg/dL, confirming intravascular (not only local pancreatic) lipolysis as a severity driver; the UFA-mediated lipotoxicity mechanism described above is central to this process.[36][37][38]

Drug-induced pancreatitis (~5% of cases): proposed mechanisms include direct acinar cell toxicity (e.g., azathioprine/6-mercaptopurine metabolites), hypersensitivity/immune-mediated injury, and indirect mechanisms such as drug-induced hypertriglyceridemia or hypercalcemia; these represent distinct pathophysiologic pathways rather than a single unifying mechanism.[39][40]

Post-ERCP pancreatitis (~5–10% of ERCPs): mechanical and hydrostatic injury to the pancreatic orifice and duct raises intraductal pressure, activating calcineurin-mediated inflammation and disrupting tight junctions (as described in the calcium-calcineurin pathway above); radiocontrast agents independently activate NF-κB and calcineurin via pathologic Ca2+ signaling in acinar cells, and thermal injury from electrocautery may contribute.[41][42]

From Local Injury to Systemic Inflammation

The transition from localized pancreatic injury to systemic disease follows a well-characterized inflammatory cascade:[43][44]

  1. Acinar cell injury releases DAMPs (HMGB1, nucleosomes, extracellular ATP, mitochondrial DNA) and activated enzymes into the interstitium
  2. Innate immune activation: neutrophils and macrophages (differentiating to pro-inflammatory M1 phenotype) infiltrate the pancreas, activating pattern recognition receptors (TLR4, TLR9, NLRP3 inflammasome, AIM2 inflammasome). Macrophage infiltration correlates more strongly with pancreatic damage than neutrophil infiltration; macrophages phagocytose necrotic acinar cell debris and activate trypsinogen intracellularly via cathepsin B, amplifying the inflammatory response through a mechanism distinct from simple cytokine release.[45][46] Recent evidence also demonstrates that neutrophil extracellular traps (NETs) activate the ZBP1-cGAS complex via mitochondrial DNA released from NET-damaged acinar cells, triggering necroptosis and amplifying inflammatory pathways — providing a direct mechanistic link between NET formation and regulated acinar cell death; cyclosporine A inhibits this axis by preventing mitochondrial DNA release. However, NETs may also play a protective role by walling off pancreatic necrosis from viable tissue, and whether NET inhibition will prove clinically beneficial remains uncertain.[47]
  3. Complement activation occurs through multiple pathways in AP, including direct trypsin-mediated cleavage of C3 and C5 generating the anaphylatoxins C3a and C5a, as well as classical and lectin pathway activation; C5a is a potent neutrophil chemoattractant, and experimental complement inhibition (e.g., soluble complement receptor 1) reduces leukocyte-endothelial interaction and organ injury.[48][49]
  4. Cytokine storm: release of IL-1β, IL-6, IL-8, IL-18, TNF-α, and MCP-1; anti-inflammatory cytokines (IL-10) modulate but may not counterbalance the response
  5. Endothelial activation and capillary leak: transendothelial leukocyte migration, microcirculatory failure, increased capillary permeability to plasma proteins (including non-albumin proteins), loss of oncotic pressure, and third-spacing of fluid. Angiopoietin-2, a regulator of endothelial permeability, is elevated on admission in patients who develop persistent organ failure; a meta-analysis of 7 studies (n = 650) found pooled sensitivity of 0.93 and specificity of 0.85 (AUC 0.95) for predicting organ failure, providing a mechanistic link between endothelial activation and capillary leak.[50][51]
  6. SIRS and organ failure: uncontrolled systemic inflammation leads to pulmonary edema/ARDS, prerenal azotemia and acute kidney injury, and cardiovascular collapse

A capillary permeability model proposed by Komara et al. (2020), based on sequential biomarker analysis in 57 patients with severe AP, suggests the SIRS-to-MOF transition is driven by progressive capillary leak of plasma proteins; in this cohort, hemoconcentration (hematocrit rise >3 points from baseline) was associated with MOF (OR 17.7, P = 0.014), though validation in larger cohorts is needed. The 2024 American College of Gastroenterology guidelines similarly identify hemoconcentration as a marker of inadequate fluid resuscitation, providing guideline-level context for this pathophysiologic observation.[52][53]

Biphasic Course: Primary and Secondary Organ Failure

Organ failure in AP follows a biphasic pattern with distinct pathophysiology and clinical implications:[54][55]

  • Early (primary) organ failure (within the first 1–2 weeks): driven by sterile SIRS from the initial inflammatory insult; occurs in ~20% of AP patients; carries high early mortality (~16%); the therapeutic window is narrow and treatment is largely supportive
  • Late (secondary) organ failure: driven by infected pancreatic necrosis (IPN)-induced sepsis; occurs after the initial SIRS phase, often following a period of compensatory anti-inflammatory response syndrome (CARS) characterized by immunosuppression (HLA-DR suppression, increased co-inhibitory molecule expression) that facilitates bacterial translocation and secondary infection

This SIRS-to-CARS transition is thought to be accompanied by a shift in macrophage polarization from a pro-inflammatory M1 phenotype toward an immunosuppressive M2 phenotype, contributing to the immunoparalysis that permits secondary infection, though direct evidence for this polarization shift in human AP remains limited. The SIRS-to-CARS transition is clinically critical: excessive early hyperinflammation causes shock and early MOF, while subsequent immunosuppression permits bacterial translocation into necrotic tissue, leading to IPN and late sepsis-driven MOF. Primary OF is also an independent risk factor for subsequent development of IPN.

Intra-abdominal hypertension (IAH; intra-abdominal pressure ≥12 mmHg) occurs in 60–80% of patients with severe AP, driven by retroperitoneal edema, fluid collections, ascites, ileus, and iatrogenic fluid overload. Abdominal compartment syndrome (ACS; intra-abdominal pressure >20 mmHg with new organ failure) develops in up to 30% of severe AP patients and carries mortality rates of 46–75%. A 2025 meta-analysis of 14 studies (n = 1197) confirmed that IAH is a strong predictor of mortality and respiratory failure even in the absence of ACS. IAH contributes to organ failure by impairing venous return, reducing renal perfusion, elevating diaphragmatic pressure (worsening respiratory failure), and exacerbating gut barrier dysfunction.[56][57][58]

Trypsin and inflammatory mediators also activate the coagulation cascade, promoting microvascular thrombosis that may contribute to pancreatic necrosis and systemic organ injury, though the clinical significance of coagulation activation in driving systemic complications remains incompletely established.[59]

Gut Barrier Dysfunction and Bacterial Translocation

The intestine plays a pivotal role in the progression from local to systemic disease. A meta-analysis of 18 studies found that 59% of AP patients have gut barrier dysfunction.[60] The mechanisms include:

  • Splanchnic hypoperfusion and ischemia-reperfusion injury from hypovolemia and reflex vasoconstriction
  • Disruption of tight junction proteins and increased intestinal permeability
  • Apoptosis and ferroptosis of intestinal epithelial cells
  • Dysbiosis with decreased commensal bacteria and overgrowth of opportunistic pathogens (Enterobacteriaceae, Enterococcus)
  • Decreased secretory IgA and impaired mucosal immune defense

Bacterial translocation from the gut to pancreatic necrotic collections is the primary mechanism of IPN; circulating bacterial DNA representative of gut microbiota has been detected in ~69% of AP patients. Mesenteric lymph from ischemic intestine can independently exacerbate pancreatic microcirculatory disturbances and worsen pancreatitis severity.[61] However, the translocation hypothesis as the sole explanation for IPN has been questioned, as bacterial translocation is common after dental and endoscopic procedures yet rarely causes sepsis, and patients with severe ulcerative colitis rarely develop systemic sepsis despite extensive colonic ulceration.

Genetic Susceptibility Mechanisms

Genetic variants affecting the trypsin-dependent pathway are the best-characterized genetic risk factors for pancreatitis:

  • PRSS1 (cationic trypsinogen): gain-of-function mutations (e.g., R122H, N29I) cause premature trypsinogen autoactivation or resistance to degradation; autosomal dominant with ~80% penetrance; the prototypical cause of hereditary pancreatitis
  • SPINK1 (serine protease inhibitor Kazal type 1): loss-of-function mutations (e.g., N34S) reduce trypsin inhibition; acts as a disease modifier rather than independent cause
  • CTRC (chymotrypsin C): variants impair trypsinogen degradation; primarily a disease modifier accelerating progression to chronic pancreatitis
  • CFTR: mutations impair ductal bicarbonate and fluid secretion, increasing ductal calcium concentration and promoting trypsinogen activation; co-inheritance with SPINK1 mutations increases risk
  • CPA1 (carboxypeptidase A1): variants cause protein misfolding and ER stress
  • CLDN2 (claudin-2, X-linked): associated with alcohol- and smoking-related pancreatitis risk
  • CASR (calcium-sensing receptor): variants alter calcium homeostasis

These genetic pathways converge on three principal mechanisms: (1) enhanced trypsinogen activation, (2) impaired trypsin degradation/inhibition, and (3) protein misfolding with ER stress. In pediatric cohorts, genetic variants are found in ~19–27% of AP patients and are the dominant risk factor (unlike adults, where environmental factors predominate).[62][63]


Microcirculatory Failure and Pancreatic Necrosis

Pancreatic necrosis develops through microcirculatory failure driven by:

  • Endothelial injury from activated enzymes and inflammatory mediators
  • Vasoconstriction and thrombosis of intrapancreatic vessels
  • Ischemia-reperfusion injury with generation of reactive oxygen species
  • Capillary leak with interstitial edema compressing the microvasculature

The extent of necrosis correlates with disease severity and is more common in patients who develop MOF (56% vs. 23% in non-MOF patients). Necrosis is initially sterile but may become infected (typically after the first week) through bacterial translocation, transforming the clinical course from sterile SIRS-driven disease to sepsis-driven disease.

Pathophysiologic Rationale for Key Management Principles

Understanding these mechanisms directly informs clinical practice:

  • Fluid resuscitation targets the capillary leak and microcirculatory failure that drive necrosis and organ failure, though the WATERFALL trial has shifted practice toward moderate rather than aggressive resuscitation. Lactated Ringer's solution is preferred; beyond its pH-buffering properties, the calcium in LR binds ionically with circulating nonesterified fatty acids associated with severe disease, providing a direct mechanistic link to the lipotoxicity pathway described above.[64]
  • Early enteral nutrition helps maintain gut barrier integrity and reduce bacterial translocation
  • Avoidance of prophylactic antibiotics is supported by the understanding that early organ failure is sterile inflammation-driven, not infection-driven
  • Delayed CT imaging aligns with the timeline of necrosis development (5–7 days)
  • Severity prediction using SIRS criteria, CRP, and hemoconcentration reflects the underlying inflammatory and capillary leak pathophysiology
  • Calcium and mitochondrial pathways represent the most promising therapeutic targets under investigation, including ORAI1 inhibitors, MPTP inhibitors, and calcineurin inhibitors (e.g., FK506/tacrolimus). The ORAI1 inhibitor zegocractin (CM4620/Auxora) is the most clinically advanced agent in this class; a phase 2b, randomized, dose-ranging trial (CARPO) reported outcomes supporting further development in AP with SIRS.[65] CM4620 has been shown to act on multiple cell types beyond acinar cells — reducing oxidative burst in neutrophils, cytokine production in macrophages, and fibroinflammatory gene expression in stellate cells — providing a multi-cell-type rationale for ORAI1 inhibition that spans the acinar, stellate, and systemic inflammatory pathways described above.[66] However, acinar cell-specific Orai1 deletion has been shown to cause lethal dysbiosis and sepsis in mice, underscoring that dose optimization rather than complete channel blockade is likely necessary. SARAF induction has been proposed as a potentially safer alternative — SARAF is an endogenous inhibitor of store-operated Ca2+ entry that normally mediates Orai1 inactivation via interaction with STIM1. During pathological stimulation, SARAF dissociates from STIM1 and is subsequently degraded, permitting sustained toxic Ca2+ influx. SARAF overexpression protects against experimental pancreatitis while its deletion exacerbates disease, without causing the lethal dysbiosis seen with Orai1 deletion; therapeutic strategies aimed at preventing SARAF degradation or restoring its expression could therefore partially limit Ca2+ influx while preserving essential Orai1 functions.[67]
  • CFTR correctors/potentiators (e.g., elexacaftor/tezacaftor/ivacaftor), already approved for cystic fibrosis, have been proposed as potential therapeutic agents to restore ductal bicarbonate secretion impaired by alcohol, bile acids, or CFTR mutations, based on the ductal dysfunction mechanism described above; preclinical and early clinical evidence supports this concept, but no AP-specific trials have been conducted.[68][69] The TGR5 agonist INT-777 and lipase inhibition (e.g., orlistat) are additional investigational targets arising from the macrophage/bile-acid and lipotoxicity pathways described above, respectively, and have not yet been tested in human AP trials.[70]

Areas of Uncertainty, Controversy, or Guideline Disagreement

  • Whether trypsin activation is truly necessary for pancreatitis initiation remains debated; genetic mouse models in which trypsinogen activation is eliminated still develop pancreatitis, but the relative contribution of trypsin-dependent vs. trypsin-independent mechanisms in human disease is unknown
  • The relative contributions of Ca2+-dependent vs. Ca2+-independent mechanisms of MPTP opening in human disease are unclear
  • Whether gut bacterial translocation is the sole mechanism of infected necrosis is questioned; clinical observations in inflammatory bowel disease patients with severe mucosal disease but low sepsis rates challenge this hypothesis
  • The role of the NLRP3 inflammasome in determining individual susceptibility to severe disease is incompletely understood
  • Whether pharmacologic enhancement of autophagy (e.g., trehalose), calcineurin inhibition (e.g., repurposed tacrolimus), or partial ORAI1/SARAF-targeted calcium modulation will translate from experimental models to human therapy remains to be determined
  • Whether the Lactated Ringer's calcium-NEFA binding mechanism meaningfully modifies disease severity has not been validated in prospective human trials
  • The precise mechanism by which alcohol causes pancreatitis in only a minority of heavy drinkers (the "susceptibility gap") is not fully explained, though the adaptive UPR and genetic cofactors likely contribute
  • Whether post-ERCP pancreatitis prevention (e.g., rectal indomethacin, pancreatic stenting) acts primarily through calcineurin-independent anti-inflammatory mechanisms or converges on the calcineurin/pressure pathway described above is not fully established

References

  1. ↑ Mederos MA, Reber HA, Girgis MD (2021). "Acute Pancreatitis". JAMA. 325 (4): 382–390. doi:10.1001/jama.2020.20317.
  2. ↑ Frossard JL, Steer ML, Pastor CM (2008). "Acute Pancreatitis". Lancet. 371 (9607): 143–52. doi:10.1016/S0140-6736(08)60107-5.
  3. ↑ Saluja A, Dudeja V, Dawra R, Sah RP (2019). "Early Intra-Acinar Events in Pathogenesis of Pancreatitis". Gastroenterology. 156 (7): 1979–1993. doi:10.1053/j.gastro.2019.01.268.
  4. ↑ Modenbach JM, Möller C, Asgarbeik S; et al. (2025). "Biochemical Analyses of Cystatin-C Dimers and Cathepsin-B Reveals a Trypsin-Driven Feedback Mechanism in Acute Pancreatitis". Nat Commun. 16 (1): 1702. doi:10.1038/s41467-025-56875-x.
  5. ↑ Gukovskaya AS, Lerch MM, Mayerle J; et al. (2024). "Trypsin in Pancreatitis: The Culprit, a Mediator, or Epiphenomenon?". World J Gastroenterol. 30 (41): 4417–4438. doi:10.3748/wjg.v30.i41.4417.
  6. ↑ Petersen OH, Gerasimenko JV, Gerasimenko OV, Gryshchenko O, Peng S (2021). "The Roles of Calcium and ATP in the Physiology and Pathology of the Exocrine Pancreas". Physiol Rev. 101 (4): 1691–1744. doi:10.1152/physrev.00003.2021.
  7. ↑ Maléth J, Hegyi P (2016). "Ca2+ Toxicity and Mitochondrial Damage in Acute Pancreatitis: Translational Overview". Philos Trans R Soc Lond B Biol Sci. 371 (1700): 20150425. doi:10.1098/rstb.2015.0425.
  8. ↑ Wen L, Javed TA, Yimlamai D; et al. (2018). "Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice". Gastroenterology. 155 (4): 1250–1263.e5. doi:10.1053/j.gastro.2018.06.036.
  9. ↑ Saluja A, Dudeja V, Dawra R, Sah RP (2019). "Early Intra-Acinar Events in Pathogenesis of Pancreatitis". Gastroenterology. 156 (7): 1979–1993. doi:10.1053/j.gastro.2019.01.268.
  10. ↑ Wen L, Javed TA, Dobbs AK; et al. (2020). "The Protective Effects of Calcineurin on Pancreatitis in Mice Depend on the Cellular Source". Gastroenterology. 159 (3): 1036–1050.e8. doi:10.1053/j.gastro.2020.05.051.
  11. ↑ Muili KA, Wang D, Orabi AI; et al. (2013). "Bile Acids Induce Pancreatic Acinar Cell Injury and Pancreatitis by Activating Calcineurin". J Biol Chem. 288 (1): 570–80. doi:10.1074/jbc.M112.428896.
  12. ↑ Xia CC, Xu Y, Wang ZH, Xu GQ (2025). "Mitochondrial Dysfunction as a Bridge to Pathology in Acute Pancreatitis: From Molecular Insights to Novel Therapeutic Strategies". World J Gastroenterol. 31 (48): 113840. doi:10.3748/wjg.v31.i48.113840.
  13. ↑ Habtezion A, Gukovskaya AS, Pandol SJ (2019). "Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions". Gastroenterology. 156 (7): 1941–1950. doi:10.1053/j.gastro.2018.11.082.
  14. ↑ Chen F, Xu K, Han Y; et al. (2024). "Mitochondrial Dysfunction in Pancreatic Acinar Cells: Mechanisms and Therapeutic Strategies in Acute Pancreatitis". Front Immunol. 15: 1503087. doi:10.3389/fimmu.2024.1503087.
  15. ↑ Biczo G, Vegh ET, Shalbueva N; et al. (2018). "Mitochondrial Dysfunction, Through Impaired Autophagy, Leads to Endoplasmic Reticulum Stress, Deregulated Lipid Metabolism, and Pancreatitis in Animal Models". Gastroenterology. 154 (3): 689–703. doi:10.1053/j.gastro.2017.10.012.
  16. ↑ Pallagi P, Balla Z, Singh AK; et al. (2014). "The Role of Pancreatic Ductal Secretion in Protection Against Acute Pancreatitis in Mice". Crit Care Med. 42 (3): e177–e188. doi:10.1097/CCM.0000000000000101. PMID 24368347.
  17. ↑ Habtezion A, Gukovskaya AS, Pandol SJ (2019). "Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions". Gastroenterology. 156 (7): 1941–1950. doi:10.1053/j.gastro.2018.11.082.
  18. ↑ Pallagi P, Görög M, Papp N; et al. (2022). "Bile Acid- and Ethanol-Mediated Activation of Orai1 Damages Pancreatic Ductal Secretion in Acute Pancreatitis". J Physiol. 600 (7): 1631–1650. doi:10.1113/JP282203.
  19. ↑ Hegyi P, Rakonczay Z (2015). "The Role of Pancreatic Ducts in the Pathogenesis of Acute Pancreatitis". Pancreatology. 15 (4 Suppl): S13–7. doi:10.1016/j.pan.2015.03.010.
  20. ↑ Gryshchenko O, Gerasimenko JV, Peng S, Gerasimenko OV, Petersen OH (2018). "Calcium Signalling in the Acinar Environment of the Exocrine Pancreas: Physiology and Pathophysiology". J Physiol. 596 (14): 2663–2678. doi:10.1113/JP275395.
  21. ↑ Gryshchenko O, Gerasimenko JV, Gerasimenko OV, Petersen OH (2016). "Ca(2+) Signals Mediated by Bradykinin Type 2 Receptors in Normal Pancreatic Stellate Cells Can Be Inhibited by Specific Ca(2+) Channel Blockade". J Physiol. 594 (2): 281–293. doi:10.1113/JP271468.
  22. ↑ Petersen OH (2023). "The 2022 George E Palade Medal Lecture: Toxic Ca2+ Signals in Acinar, Stellate and Endogenous Immune Cells Are Important Drivers of Acute Pancreatitis". Pancreatology. 23 (1): 1–8. doi:10.1016/j.pan.2022.12.010.
  23. ↑ Noel P, Patel K, Durgampudi C; et al. (2016). "Peripancreatic Fat Necrosis Worsens Acute Pancreatitis Independent of Pancreatic Necrosis via Unsaturated Fatty Acids Increased in Human Pancreatic Necrosis Collections". Gut. 65 (1): 100–11. doi:10.1136/gutjnl-2014-308043.
  24. ↑ Patel K, Trivedi RN, Durgampudi C; et al. (2015). "Lipolysis of Visceral Adipocyte Triglyceride by Pancreatic Lipases Converts Mild Acute Pancreatitis to Severe Pancreatitis Independent of Necrosis and Inflammation". Am J Pathol. 185 (3): 808–819. doi:10.1016/j.ajpath.2014.11.019.
  25. ↑ Phillips AE, Wilson AS, Greer PJ; et al. (2023). "Relationship of Circulating Levels of Long-Chain Fatty Acids to Persistent Organ Failure in Acute Pancreatitis". Am J Physiol Gastrointest Liver Physiol. 325 (3): G279–G285. doi:10.1152/ajpgi.00074.2023.
  26. ↑ Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
  27. ↑ Mayerle J, Sendler M, Hegyi E; et al. (2019). "Genetics, Cell Biology, and Pathophysiology of Pancreatitis". Gastroenterology. 156 (7): 1951–1968.e1. doi:10.1053/j.gastro.2018.11.081.
  28. ↑ Zhang J, Chen H, Wang Y; et al. (2026). "Cell Death and Its Interaction With Mitochondrial Dysfunction in Pathogenesis of Acute Pancreatitis: A Comprehensive Review". Apoptosis. 31 (2): 66. doi:10.1007/s10495-026-02288-0.
  29. ↑ Fortunato F, Bürgers H, Bergmann F; et al. (2009). "Impaired Autolysosome Formation Correlates With Lamp-2 Depletion: Role of Apoptosis, Autophagy, and Necrosis in Pancreatitis". Gastroenterology. 137 (1): 350–60. doi:10.1053/j.gastro.2009.04.003.
  30. ↑ Perides G, Laukkarinen JM, Vassileva G, Steer ML (2010). "Biliary Acute Pancreatitis in Mice Is Mediated by the G-Protein-Coupled Cell Surface Bile Acid Receptor Gpbar1". Gastroenterology. 138 (2): 715–25. doi:10.1053/j.gastro.2009.10.052.
  31. ↑ Tran QT, Tran VH, Sendler M; et al. (2021). "Role of Bile Acids and Bile Salts in Acute Pancreatitis: From the Experimental to Clinical Studies". Pancreas. 50 (1): 3–11. doi:10.1097/MPA.0000000000001706.
  32. ↑ Zhang ZY, Guo XL, Liu JT; et al. (2024). "Conjugated Bile Acids Alleviate Acute Pancreatitis Through Inhibition of TGR5 and NLRP3 Mediated Inflammation". J Transl Med. 22 (1): 1124. doi:10.1186/s12967-024-05922-0.
  33. ↑ Guo C, Xie S, Chi Z; et al. (2016). "Bile Acids Control Inflammation and Metabolic Disorder Through Inhibition of NLRP3 Inflammasome". Immunity. 45 (4): 802–816. doi:10.1016/j.immuni.2016.09.008.
  34. ↑ Wang F, Görgülü K, Algül H, Hu LH (2026). "The Role of Alcohol in Pancreatic Diseases: A Comprehensive Perspective". Gastroenterology. 170 (2): 268–286. doi:10.1053/j.gastro.2025.08.025.
  35. ↑ Farooq A, Richman CM, Swain SM; et al. (2021). "The Role of Phosphate in Alcohol-Induced Experimental Pancreatitis". Gastroenterology. 161 (3): 982–995.e2. doi:10.1053/j.gastro.2021.05.048.
  36. ↑ Rajalingamgari P, Khatua B, Summers MJ; et al. (2024). "Prospective Observational Study and Mechanistic Evidence Showing Lipolysis of Circulating Triglycerides Worsens Hypertriglyceridemic Acute Pancreatitis". J Clin Invest. 135 (1): e184785. doi:10.1172/JCI184785. PMID 39509346 Check |pmid= value (help).
  37. ↑ Phillips AE, Wilson AS, Greer PJ; et al. (2023). "Relationship of Circulating Levels of Long-Chain Fatty Acids to Persistent Organ Failure in Acute Pancreatitis". Am J Physiol Gastrointest Liver Physiol. 325 (3): G279–G285. doi:10.1152/ajpgi.00074.2023.
  38. ↑ Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
  39. ↑ Mederos MA, Reber HA, Girgis MD (2021). "Acute Pancreatitis". JAMA. 325 (4): 382–390. doi:10.1001/jama.2020.20317.
  40. ↑ Forsmark CE, Vege SS, Wilcox CM (2016). "Acute Pancreatitis". N Engl J Med. 375 (20): 1972–1981. doi:10.1056/NEJMra1505202.
  41. ↑ Jin S, Orabi AI, Le T; et al. (2015). "Exposure to Radiocontrast Agents Induces Pancreatic Inflammation by Activation of Nuclear Factor-κB, Calcium Signaling, and Calcineurin". Gastroenterology. 149 (3): 753–764.e11. doi:10.1053/j.gastro.2015.05.004.
  42. ↑ Wen L, Javed TA, Yimlamai D; et al. (2018). "Transient High Pressure in Pancreatic Ducts Promotes Inflammation and Alters Tight Junctions via Calcineurin Signaling in Mice". Gastroenterology. 155 (4): 1250–1263.e5. doi:10.1053/j.gastro.2018.06.036.
  43. ↑ Sendler M, van den Brandt C, Glaubitz J; et al. (2020). "NLRP3 Inflammasome Regulates Development of Systemic Inflammatory Response and Compensatory Anti-Inflammatory Response Syndromes in Mice With Acute Pancreatitis". Gastroenterology. 158 (1): 253–269.e14. doi:10.1053/j.gastro.2019.09.040.
  44. ↑ Venkatesh K, Glenn H, Delaney A, Andersen CR, Sasson SC (2022). "Fire in the Belly: A Scoping Review of the Immunopathological Mechanisms of Acute Pancreatitis". Front Immunol. 13: 1077414. doi:10.3389/fimmu.2022.1077414.
  45. ↑ Sendler M, Weiss FU, Golchert J; et al. (2018). "Cathepsin B-Mediated Activation of Trypsinogen in Endocytosing Macrophages Increases Severity of Pancreatitis in Mice". Gastroenterology. 154 (3): 704–718.e10. doi:10.1053/j.gastro.2017.10.018.
  46. ↑ Saluja A, Dudeja V, Dawra R, Sah RP (2019). "Early Intra-Acinar Events in Pathogenesis of Pancreatitis". Gastroenterology. 156 (7): 1979–1993. doi:10.1053/j.gastro.2019.01.268.
  47. ↑ Zhang H, Wang Z, Lu J; et al. (2026). "Neutrophil Extracellular Traps Prime the ZBP1-cGAS Sensor Complex, Triggering Necroptosis and Inflammatory Injury in Acute Pancreatitis". Int J Biol Sci. 22 (5): 2398–2417. doi:10.7150/ijbs.122290.
  48. ↑ Bettac L, Denk S, Seufferlein T, Huber-Lang M (2017). "Complement in Pancreatic Disease-Perpetrator or Savior?". Front Immunol. 8: 15. doi:10.3389/fimmu.2017.00015.
  49. ↑ Hartwig W, Klafs M, Kirschfink M; et al. (2006). "Interaction of Complement and Leukocytes in Severe Acute Pancreatitis: Potential for Therapeutic Intervention". Am J Physiol Gastrointest Liver Physiol. 291 (5): G844–G850. doi:10.1152/ajpgi.00016.2006.
  50. ↑ Whitcomb DC, Muddana V, Langmead CJ; et al. (2010). "Angiopoietin-2, a Regulator of Vascular Permeability in Inflammation, Is Associated With Persistent Organ Failure in Patients With Acute Pancreatitis From the United States and Germany". Am J Gastroenterol. 105 (10): 2287–92. doi:10.1038/ajg.2010.183.
  51. ↑ Lv Y, Yao Y, Liu Q, Lei J (2021). "Accuracy of Angiopoietin-2 for Predicting Organ Failure in Patients With Acute Pancreatitis: A Systematic Review and Meta-Analysis". J Int Med Res. 49 (2): 300060520986708. doi:10.1177/0300060520986708.
  52. ↑ Komara NL, Paragomi P, Greer PJ; et al. (2020). "Severe Acute Pancreatitis: Capillary Permeability Model Linking Systemic Inflammation to Multiorgan Failure". Am J Physiol Gastrointest Liver Physiol. 319 (5): G573–G583. doi:10.1152/ajpgi.00285.2020.
  53. ↑ Tenner S, Vege SS, Sheth SG; et al. (2024). "American College of Gastroenterology Guidelines: Management of Acute Pancreatitis". Am J Gastroenterol. 119 (3): 419–437. doi:10.14309/ajg.0000000000002645.
  54. ↑ Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
  55. ↑ Padhan RK, Jain S, Agarwal S; et al. (2018). "Primary and Secondary Organ Failures Cause Mortality Differentially in Acute Pancreatitis and Should Be Distinguished". Pancreas. 47 (3): 302–307. doi:10.1097/MPA.0000000000000998.
  56. ↑ Darweesh M, El-Kurdi B, Mahfouz R; et al. (2025). "Intra-Abdominal Hypertension Is a Strong Predictor of Mortality and Poor Clinical Outcome in Severe Acute Pancreatitis". Dig Dis Sci. 70 (3): 1233–1245. doi:10.1007/s10620-024-08749-3.
  57. ↑ van Brunschot S, Bakker OJ, Besselink MG; et al. (2012). "Treatment of Necrotizing Pancreatitis". Clin Gastroenterol Hepatol. 10 (11): 1190–201. doi:10.1016/j.cgh.2012.05.005.
  58. ↑ "IAP/APA Evidence-Based Guidelines for the Management of Acute Pancreatitis". Pancreatology. 13 (4 Suppl 2): e1–15. 2013. doi:10.1016/j.pan.2013.07.063.
  59. ↑ Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
  60. ↑ Akshintala VS, Talukdar R, Singh VK, Goggins M (2019). "The Gut Microbiome in Pancreatic Disease". Clin Gastroenterol Hepatol. 17 (2): 290–295. doi:10.1016/j.cgh.2018.08.045.
  61. ↑ Garg PK, Singh VP (2019). "Organ Failure Due to Systemic Injury in Acute Pancreatitis". Gastroenterology. 156 (7): 2008–2023. doi:10.1053/j.gastro.2018.12.041.
  62. ↑ Ahmed F, Abu-El-Haija M (2025). "Acute Pancreatitis in Children: It's Not Just a Simple Attack". Gastroenterology. 169 (4): 572–584. doi:10.1053/j.gastro.2025.04.001.
  63. ↑ Uc A, Husain SZ (2019). "Pancreatitis in Children". Gastroenterology. 156 (7): 1969–1978. doi:10.1053/j.gastro.2018.12.043.
  64. ↑ Tenner S, Vege SS, Sheth SG; et al. (2024). "American College of Gastroenterology Guidelines: Management of Acute Pancreatitis". Am J Gastroenterol. 119 (3): 419–437. doi:10.14309/ajg.0000000000002645.
  65. ↑ Sutton R, Garg PK, Miller J; et al. (2026). "Zegocractin for Acute Pancreatitis With Systemic Inflammatory Response Syndrome: A Randomized, Controlled, Dose-Ranging, Phase 2b Trial". EClinicalMedicine. 93: 103757. doi:10.1016/j.eclinm.2026.103757.
  66. ↑ Waldron RT, Chen Y, Pham H; et al. (2019). "The Orai Ca2+ Channel Inhibitor CM4620 Targets Both Parenchymal and Immune Cells to Reduce Inflammation in Experimental Acute Pancreatitis". J Physiol. 597 (12): 3085–3105. doi:10.1113/JP277856.
  67. ↑ Son A, Ahuja M, Schwartz DM; et al. (2019). "Ca2+ Influx Channel Inhibitor SARAF Protects Mice From Acute Pancreatitis". Gastroenterology. 157 (6): 1660–1672.e2. doi:10.1053/j.gastro.2019.08.042.
  68. ↑ Sarkar P, Lin WY, Movahed Abtahi A, Chung WY, Muallem S (2026). "Pancreatitis: Correcting CFTR Expression and Function as a Promising Effective Treatment". Front Physiol. 17: 1813824. doi:10.3389/fphys.2026.1813824.
  69. ↑ Maléth J, Balázs A, Pallagi P; et al. (2015). "Alcohol Disrupts Levels and Function of the Cystic Fibrosis Transmembrane Conductance Regulator to Promote Development of Pancreatitis". Gastroenterology. 148 (2): 427–39.e16. doi:10.1053/j.gastro.2014.11.002.
  70. ↑ Li B, Yang N, Li C; et al. (2018). "INT-777, a Bile Acid Receptor Agonist, Extenuates Pancreatic Acinar Cells Necrosis in a Mouse Model of Acute Pancreatitis". Biochem Biophys Res Commun. 503 (1): 38–44. doi:10.1016/j.bbrc.2018.05.120.
Retrieved from "https://www.wikidoc.org/index.php?title=Acute_pancreatitis_pathophysiology&oldid=1745275"