Acute pancreatitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]; Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[3] Raviteja Guddeti, M.B.B.S. [4] Tarek Nafee, M.D. [5]

Acute pancreatitis is an acute inflammatory injury of the pancreas that ranges from a mild, self-limited illness to necrotizing disease with persistent organ failure. The diagnosis requires at least 2 of 3 features: characteristic abdominal pain, serum lipase or amylase at least 3 times the upper limit of normal, or characteristic imaging findings; imaging is not routinely required when the clinical and biochemical criteria are already met.^[1][2]

Gallstone disease and prolonged heavy alcohol exposure are the leading causes. Initial care focuses on determining the etiology, identifying patients at risk for deterioration, goal-directed intravenous hydration, analgesia, early oral or enteral nutrition, and treatment of complications. Prophylactic antibiotics, routine early CT, routine urgent ERCP in the absence of cholangitis or persistent biliary obstruction, prolonged fasting, and early open necrosectomy are not recommended.^[3][4][5]

Clinical dimension	Quick-glance summary
Diagnosis	At least 2 of 3: characteristic pain, lipase or amylase ≥3 times the upper limit of normal, or characteristic imaging
Most common causes	Gallstones and prolonged heavy alcohol exposure; evaluate triglycerides, calcium, medications, recent ERCP, structural disease, autoimmune disease, tumors, trauma, infection, and genetic susceptibility when appropriate
Severity	Mild: no organ failure or local/systemic complications; moderately severe: transient organ failure and/or local or systemic complications; severe: persistent organ failure for more than 48 hours
Initial priorities	Determine etiology, monitor for organ dysfunction, provide goal-directed lactated Ringer’s solution and analgesia, initiate early feeding as tolerated, and arrange cause-specific treatment
Major complications	Pancreatic or peripancreatic necrosis and collections, infection, hemorrhage, venous thrombosis, biliary or gastric obstruction, exocrine insufficiency, diabetes, recurrent acute pancreatitis, and chronic pancreatitis

Acute pancreatitis was established as a distinct clinicopathologic entity by Reginald H. Fitz in 1889, when he organized the clinical and postmortem findings from 53 patients and described hemorrhagic, suppurative, and gangrenous forms.^[6] Subsequent advances shifted care from early operative exploration and prolonged pancreatic rest toward standardized severity classification, early nutrition, selective imaging, and delayed minimally invasive treatment of necrosis.

Year	Milestone	Clinical importance
1889	Fitz’s clinicopathologic description	Established acute pancreatitis as a recognizable disease and described major morphologic patterns.[6]
1974	Ranson prognostic signs	Introduced a structured clinical approach to early severity prediction.[7]
1992–1993	Original Atlanta Classification	Standardized clinical definitions and terminology for severity and complications.[8]
2012–2013	Revised Atlanta Classification	Defined early and late phases, organ-failure-based severity, interstitial edematous and necrotizing subtypes, and four standardized collection types.[1]
2010s–2020s	Evidence-based supportive and step-up care	Established early feeding, avoidance of indiscriminate antibiotics and ERCP, moderate rather than aggressive hydration, and delayed minimally invasive intervention for necrosis.[4][5]

Acute pancreatitis is classified by clinical phase, clinical severity, morphologic subtype, and the type of pancreatic or peripancreatic collection. The early phase usually encompasses the first week and is dominated by the systemic inflammatory response and organ dysfunction; the late phase may persist for weeks to months and is characterized by ongoing organ failure and local complications. Morphologically, acute pancreatitis is classified as interstitial edematous pancreatitis or necrotizing pancreatitis.^[1]

Revised Atlanta severity	Definition	Typical clinical implication
Mild	No organ failure and no local or systemic complications	Usually self-limited, with recovery during the first week
Moderately severe	Transient organ failure that resolves within 48 hours and/or local or systemic complications without persistent organ failure	Requires closer monitoring and may require treatment of local complications
Severe	Persistent organ failure lasting more than 48 hours; may involve one or multiple organ systems	High risk of critical illness, prolonged hospitalization, and death

Local collections are classified as acute peripancreatic fluid collections, pancreatic pseudocysts, acute necrotic collections, or walled-off necrosis according to the underlying morphologic subtype, contents, encapsulation, and time from symptom onset. Organ failure is defined using the modified Marshall score; a score of at least 2 in the respiratory, renal, or cardiovascular system indicates organ failure.^[1][9]

Acute pancreatitis begins when an initiating insult disrupts pancreatic acinar and ductal cell homeostasis. Sustained intracellular calcium elevation, premature digestive-enzyme activation, mitochondrial dysfunction, impaired autophagy, endoplasmic-reticulum stress, ductal bicarbonate failure, lipotoxicity, and regulated cell-death pathways interact to produce local pancreatic injury.^[10]

Key steps include:

• Acinar-cell injury and intra-acinar zymogen activation
• Mitochondrial ATP depletion and failure of calcium homeostasis
• Impaired autophagic clearance of damaged organelles and activated enzymes
• Acinar necrosis with release of damage-associated molecular patterns
• Neutrophil, macrophage, complement, inflammasome, and cytokine activation
• Endothelial injury, capillary leak, pancreatic microcirculatory failure, and thrombosis
• Progression from local inflammation to systemic inflammatory response syndrome, shock, respiratory failure, acute kidney injury, and multiorgan failure

Gallstone obstruction, alcohol toxicity, hypertriglyceridemia-related lipotoxicity, hypercalcemia, ductal obstruction, medications, and genetic variants initiate injury through partly distinct upstream pathways but converge on common inflammatory and cell-death mechanisms.

Acute pancreatitis is most commonly caused by gallstones or prolonged heavy alcohol exposure, but a systematic etiologic evaluation is required because prevention of recurrence depends on correcting the underlying cause.^[11]

Etiologic category	Examples	Important clinical points
Biliary	Gallstones, biliary sludge, microlithiasis	The most common cause; evaluate with transabdominal ultrasound and liver biochemical tests
Alcohol associated	Prolonged heavy alcohol exposure, often with tobacco and genetic cofactors	Alcohol should not be assigned as the cause solely because a patient reports moderate use; alternative etiologies still require evaluation
Metabolic	Severe hypertriglyceridemia, hypercalcemia	A triglyceride level above 1,000 mg/dL is strongly suggestive when gallstones and alcohol are absent; identify the cause of hypercalcemia
Iatrogenic or traumatic	Post-ERCP pancreatitis, abdominal trauma, postoperative or ischemic injury	Timing and procedural or injury history are central to diagnosis
Drug induced	Selected medications with a credible temporal relationship and published evidence	A diagnosis of exclusion; review latency, competing causes, and improvement after withdrawal rather than relying on an uncritical medication list
Autoimmune	Type 1 IgG4-related autoimmune pancreatitis, type 2 autoimmune pancreatitis	Often has characteristic imaging or systemic features; autoimmune pancreatitis more often presents as a chronic or mass-forming process but can mimic acute pancreatitis
Obstructive or anatomic	Pancreas divisum, ampullary or pancreatic tumor, ductal stricture, choledochocele	Consider particularly in recurrent disease or in patients older than 40 years with otherwise unexplained pancreatitis
Genetic	Pathogenic or susceptibility variants involving PRSS1, SPINK1, CFTR, CTRC, CPA1, and other genes	Consider in early-onset, recurrent, familial, or otherwise unexplained pancreatitis
Infectious and other uncommon causes	Selected viral, bacterial, fungal, or parasitic infections; vascular and systemic inflammatory disorders	Require compatible clinical context; avoid attributing nonspecific enzyme elevation to pancreatitis without meeting diagnostic criteria
Idiopathic	No cause identified after standard evaluation	Repeat ultrasound, MRI/MRCP, and/or endoscopic ultrasound can reveal occult biliary, ductal, or neoplastic disease

Acute pancreatitis should be differentiated from other causes of acute epigastric or upper abdominal pain, systemic inflammation, and elevated pancreatic enzymes. Lipase elevation is not specific when the clinical presentation is discordant, and myocardial, vascular, gastrointestinal, hepatobiliary, renal, metabolic, and pulmonary emergencies must not be missed.

Condition	Features that favor the alternative diagnosis
Acute cholecystitis or acute cholangitis	Right upper-quadrant predominance, sonographic gallbladder inflammation, jaundice, cholestatic laboratory pattern, or biliary sepsis; these disorders may coexist with biliary pancreatitis
Perforated peptic ulcer	Sudden severe pain, peritoneal signs, and free intraperitoneal air
Mesenteric ischemia	Pain out of proportion to examination, vascular risk factors, elevated lactate, and vascular or bowel abnormalities on CT angiography
Bowel obstruction	Colicky pain, obstipation, marked distension, transition point, and dilated bowel loops
Acute coronary syndrome or pericarditis	Ischemic or positional symptoms, diagnostic ECG changes, and a compatible troponin pattern
Aortic aneurysm, dissection, or other vascular catastrophe	Abrupt pain, pulse or blood-pressure asymmetry, hemodynamic instability, and diagnostic vascular imaging
Diabetic ketoacidosis	Hyperglycemia, anion-gap metabolic acidosis, ketosis, and improvement with metabolic treatment; lipase may be elevated without pancreatitis
Renal colic or pyelonephritis	Flank-predominant pain, hematuria or pyuria, urinary symptoms, and urinary-tract imaging findings
Lower-lobe pneumonia or pulmonary embolism	Respiratory symptoms, hypoxemia, pleuritic pain, and diagnostic chest or pulmonary vascular imaging

Acute pancreatitis is one of the most common gastrointestinal causes of acute hospitalization, and its incidence has increased globally over recent decades.^[12]

• In 2021, an estimated 2.75 million cases and 122,420 deaths occurred worldwide, with substantial geographic and socioeconomic variation.^[13]
• Reported incidence in high-income countries is approximately 34 cases per 100,000 person-years, although estimates vary by case definition, population, and etiology.^[9]
• The United States records approximately 300,000 hospital admissions for acute pancreatitis each year, with substantial health-care utilization and cost.^[2]
• Gallstone-related disease becomes more common with increasing age and is more frequent among women in many populations; alcohol-associated disease is more frequent among men, although these patterns vary.
• Obesity, metabolic disease, alcohol exposure, tobacco use, medication patterns, access to care, and diagnostic practices contribute to temporal and geographic variation.
• Racial and ethnic differences reported in United States cohorts should be interpreted in the context of structural inequities, comorbidities, environmental exposures, and access to timely care rather than as evidence of biologic racial causation.^[4]

Acute pancreatitis is more likely to occur in patients with gallstones, prolonged heavy alcohol exposure, tobacco use, severe hypertriglyceridemia, hypercalcemia, obesity or metabolic syndrome, selected medication exposures, recent ERCP, structural pancreaticobiliary disease, or genetic susceptibility.

Risk factors for a more severe course include:

• Persistent systemic inflammatory response syndrome
• Older age, frailty, and clinically important comorbidities
• Obesity
• Altered mental status
• High or rising blood urea nitrogen and hematocrit
• Pleural effusion, pulmonary infiltrates, and extensive extrapancreatic collections
• Early or evolving respiratory, renal, or cardiovascular dysfunction^[2]

Risk factors for recurrence or progression to chronic pancreatitis include an untreated biliary cause, continued heavy alcohol exposure, tobacco smoking, severe hypertriglyceridemia, genetic susceptibility, structural ductal disease, and a prior necrotizing or recurrent episode.^[4]

Acute pancreatitis is mild and self-limited in approximately 80% of patients, but a minority develop transient or persistent organ failure, necrosis, infection, or other local complications.^[14]

The clinical course is often biphasic:

• Early phase: Systemic inflammation, capillary leak, and organ failure drive morbidity and early deaths. Morphologic changes may still be evolving, so early CT can underestimate necrosis.
• Late phase: Persistent organ failure and local complications become dominant. Infected necrosis often becomes clinically apparent after the first 1–2 weeks, although the timing varies.^[15][16]

Major complications include:

• Acute peripancreatic fluid collection, acute necrotic collection, pseudocyst, and walled-off necrosis
• Sterile or infected pancreatic and peripancreatic necrosis
• Acute respiratory failure, acute kidney injury, shock, and multiorgan failure
• Splanchnic venous thrombosis, pseudoaneurysm, hemorrhage, and bowel ischemia or fistula
• Biliary, gastric-outlet, or intestinal obstruction
• Abdominal compartment syndrome
• Pancreatic duct disruption and disconnected pancreatic duct syndrome
• Malnutrition, pancreatic exocrine insufficiency, and pancreatogenic diabetes
• Recurrent acute pancreatitis and progression to chronic pancreatitis

Overall mortality is approximately 1–2%, but it rises substantially with persistent organ failure and infected necrosis.^[17] Recurrent acute pancreatitis develops in a clinically important minority of patients, and approximately 10% progress to chronic pancreatitis after a first episode, with a markedly greater risk after recurrent episodes.^[18][4] Unexplained acute pancreatitis, particularly in a patient older than 40 years, should prompt consideration of an occult pancreatic tumor.

Acute pancreatitis is diagnosed when at least 2 of the following 3 criteria are present:

• Characteristic acute upper abdominal pain
• Serum lipase and/or amylase at least 3 times the upper limit of normal
• Characteristic findings on cross-sectional imaging^[1]

When characteristic pain and enzyme elevation are both present, CT is generally unnecessary solely to establish the diagnosis. Diagnostic evaluation should simultaneously identify the etiology and detect organ dysfunction or complications.

Acute pancreatitis typically presents with acute, persistent epigastric or upper abdominal pain that often radiates to the back and may be accompanied by nausea and vomiting.

Important history includes:

• Onset, severity, character, radiation, and progression of pain
• Nausea, vomiting, inability to tolerate oral intake, fever, dyspnea, oliguria, confusion, or syncope
• Prior pancreatitis, gallstones, biliary colic, jaundice, or cholecystectomy
• Amount and duration of alcohol use and tobacco exposure
• Recent ERCP, abdominal trauma, surgery, or ischemic event
• New or recently changed medications
• Hypertriglyceridemia, hypercalcemia, autoimmune disease, infection, or malignancy
• Family history and age at first episode, particularly in recurrent or early-onset disease

Acute pancreatitis most commonly causes epigastric tenderness, which may be accompanied by guarding, abdominal distension, or decreased bowel sounds from ileus.

Examination should assess:

• Temperature, heart rate, blood pressure, respiratory rate, oxygen saturation, mental status, and urine output
• Volume depletion, capillary refill, and peripheral perfusion
• Peritoneal signs suggesting severe inflammation or an alternative surgical emergency
• Jaundice or right upper-quadrant findings suggesting biliary obstruction or cholangitis
• Respiratory distress, pleural effusion, or pulmonary edema
• Rare flank or periumbilical ecchymosis; Grey Turner and Cullen signs indicate retroperitoneal or intraperitoneal bleeding but are neither sensitive nor specific

Acute pancreatitis is supported by a serum lipase or amylase concentration at least 3 times the upper limit of normal. Lipase is preferred because it remains elevated longer and performs better in delayed presentation, alcohol-associated pancreatitis, and hypertriglyceridemia-associated pancreatitis; the magnitude of elevation does not reliably indicate severity.^[2][4]

Additional studies should be selected to determine etiology and assess severity:

• Complete blood count, electrolytes, glucose, blood urea nitrogen, creatinine, liver biochemical tests, calcium, and triglycerides
• Arterial or venous blood gas and lactate when shock, respiratory failure, or severe metabolic derangement is suspected
• C-reactive protein as a delayed inflammatory marker; it is not required to establish the diagnosis
• Blood cultures when sepsis, cholangitis, or infected necrosis is suspected
• Immunoglobulin G4 only when the clinical and imaging pattern suggests type 1 autoimmune pancreatitis

Acute pancreatitis has no diagnostic electrocardiographic pattern. An ECG and cardiac biomarkers should be obtained when the presentation could represent acute coronary syndrome; nonspecific ST-segment or T-wave abnormalities may occur during acute pancreatitis and should not be assumed benign without appropriate clinical evaluation.

Acute pancreatitis has no specific diagnostic chest radiograph finding. Chest radiography may demonstrate a left-sided or bilateral pleural effusion, basilar atelectasis, pulmonary infiltrates, or acute respiratory distress syndrome and can help identify alternative diagnoses such as pneumonia or perforated viscus.

Acute pancreatitis may be characterized on contrast-enhanced CT by pancreatic enlargement, altered or absent pancreatic enhancement, peripancreatic inflammatory change, fluid collections, and local vascular or gastrointestinal complications. CT should be reserved for diagnostic uncertainty, failure to improve or clinical deterioration after approximately 48–72 hours, suspected necrosis or another complication, or procedural planning; CT performed during the first 24–48 hours may underestimate evolving necrosis.^[19][2]

Acute pancreatitis should generally be evaluated with transabdominal ultrasound to identify gallstones, biliary sludge, and common bile duct dilation, although bowel gas frequently limits visualization of the pancreas. Repeat ultrasound, endoscopic ultrasound, or MRI/MRCP may identify occult microlithiasis, choledocholithiasis, structural disease, or small tumors in otherwise unexplained pancreatitis.^[2][5]

Acute pancreatitis can be further evaluated with MRI/MRCP when CT is contraindicated or when ductal, biliary, or collection characterization is required. Secretin-enhanced MRCP and endoscopic ultrasound are especially useful in selected patients with recurrent or idiopathic disease. ERCP is primarily therapeutic rather than a routine diagnostic test and should not be performed solely to confirm acute pancreatitis.

Test	Principal role	Main limitation or caution
Serum lipase	Supports diagnosis when ≥3 times the upper limit of normal	Elevation is not fully specific, and the degree of elevation does not grade severity
Transabdominal ultrasound	First-line assessment for gallstones and biliary dilation	Limited pancreatic visualization because of bowel gas and body habitus
Contrast-enhanced CT	Evaluates uncertain diagnosis, necrosis, collections, vascular complications, deterioration, and procedural anatomy	Routine early CT adds radiation and contrast exposure and may underestimate early necrosis
MRI/MRCP	Characterizes ducts, biliary disease, necrosis, and collections without ionizing radiation	Longer examination, reduced availability, and less suitability for some unstable patients
Endoscopic ultrasound	Detects microlithiasis, small common bile duct stones, small tumors, and subtle structural causes	Invasive and operator dependent; generally used after the acute presentation or when standard evaluation is unrevealing
ERCP	Therapeutic biliary decompression in cholangitis or selected cases of persistent obstruction	Can cause or worsen pancreatitis and is not a routine diagnostic test

Acute pancreatitis is treated with early supportive care, close reassessment for organ dysfunction, cause-specific therapy, and selective intervention for biliary disease, infected necrosis, symptomatic collections, or other complications.

Acute pancreatitis requires individualized fluid therapy, analgesia, nutrition, and organ support rather than a disease-specific medication for the inflammatory process.

• Monitoring: Reassess vital signs, urine output, mental status, oxygenation, blood urea nitrogen, creatinine, and hematocrit frequently during the first 6–24 hours; admit high-risk patients to a monitored or intensive-care setting.
• Fluids: Use goal-directed, moderately aggressive crystalloid resuscitation, with lactated Ringer’s solution generally preferred. Avoid fixed aggressive hydration, particularly in patients with cardiac or renal disease. The WATERFALL trial found more fluid overload without improved outcomes from aggressive compared with moderate resuscitation.^[20]
• Analgesia and antiemetics: Provide adequate pain and nausea control; opioid analgesia may be used when clinically appropriate.
• Nutrition: Begin a low-fat solid oral diet within 24–48 hours as tolerated. If oral intake is not tolerated, use enteral rather than parenteral nutrition; nasogastric feeding is generally acceptable.^[21]
• Antibiotics: Do not administer prophylactic antibiotics for predicted severe disease or sterile necrosis. Give therapeutic antibiotics for cholangitis, infected necrosis, or another proven or strongly suspected infection.
• Organ support: Treat hypoxemia, shock, acute kidney injury, electrolyte abnormalities, hyperglycemia, and other organ dysfunction according to critical-care principles.

Acute pancreatitis rarely requires immediate open surgery; endoscopic, radiologic, laparoscopic, and minimally invasive surgical procedures are selected according to etiology, complications, and timing.

• ERCP: Perform urgent ERCP for acute biliary pancreatitis complicated by cholangitis. In the absence of cholangitis, routine urgent ERCP is not recommended; persistent common bile duct obstruction requires individualized evaluation.
• Cholecystectomy: Perform same-admission laparoscopic cholecystectomy for mild gallstone pancreatitis when the patient is fit for surgery. In necrotizing pancreatitis, delay cholecystectomy until inflammation and collections have resolved or stabilized. A 2026 nationwide Swedish cohort found recurrent pancreatitis in 3.4% after index-admission cholecystectomy, 4.9% after ERCP alone, and 17.5% after no index intervention; other gallstone complications remained substantially more common after ERCP alone than after cholecystectomy.^[22]
• Necrosis and collections: Observe asymptomatic sterile necrosis and collections. Intervene for infected necrosis or persistent symptoms and complications such as obstruction, nutritional failure, fistula, bleeding, or ongoing organ dysfunction.
• Step-up approach: When intervention is required, begin with endoscopic or percutaneous drainage and proceed to endoscopic or minimally invasive necrosectomy only if necessary. Delay intervention until the collection is walled off, usually approximately 4 weeks, when the patient’s condition permits.^[23][24]

Acute pancreatitis is not a vaccine-preventable disease, and no vaccine is applicable. Prevention depends on reducing modifiable exposures, preventing post-ERCP pancreatitis, identifying the cause of every episode, and avoiding ineffective or harmful interventions.

Prevention level	Strategies
Primary	Avoid prolonged heavy alcohol exposure and tobacco; treat severe hypertriglyceridemia and hypercalcemia; maintain a healthy weight; use ERCP only when indicated and apply evidence-based post-ERCP prophylaxis in appropriate patients
Secondary	Determine and correct the cause after the first episode; perform same-admission cholecystectomy for mild gallstone pancreatitis; stop a credible offending medication; support alcohol and smoking cessation; control triglycerides; evaluate recurrent, early-onset, familial, or idiopathic pancreatitis for structural and genetic causes
Tertiary	Prevent disability from established disease by treating infected necrosis and symptomatic collections with a multidisciplinary step-up approach, supporting nutrition and rehabilitation, and screening for pancreatic exocrine insufficiency, diabetes, and recurrent or chronic pancreatitis
Quaternary	Avoid routine early CT when diagnostic criteria are already met, prophylactic antibiotics for sterile disease, routine urgent ERCP without cholangitis or persistent obstruction, prolonged fasting, overly aggressive fluid resuscitation, and premature open necrosectomy

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

Dutch physician and anatomist, Nicholaes Tulp, gave the first clear description of acute pancreatitis in 1652. The first systemic analysis of acute pancreatitis was presented by Reginald Huber Fitz in 1889. During the 20th century, there were many theories about whether surgery should be the preferred initial approach to the treatment of acute pancreatitis. Hans Chiari in 1896 proposed that the basic mechanism of the disease was autodigestion of pancreas. The father of modern anatomical pathology, Giovanni Battista Morgagni, gave the first description of pancreatic pseudocysts.

The historical landmarks in the diagnostic evaluation and management of acute pancreatitis are as follows:^{[1] [2]}

• In the 16th century, Sylvius Franciscus de la Boe Sylvius found that the pancreas discharged a fluid that mixed with the partly digested food and bile in the intestine causing an effervescence (“effervescentia intestinalis”) which liquefied food.
• In the 16th century, Regnier de Graaf of Delft devised novel surgical techniques to create pancreatic fistulas (center) to collect this juice for analysis.
• In 1642, Johannes Wirsung of Padua first described the pancreatic duct and the concept of the pancreas as a secretory organ.
• In 1652, Nicholaes Tulp of Amsterdam is credited with the first description of acute pancreatitis.
• In 1737, Giovanni Santorini of Venice identified a second, accessory duct and was credited with primacy in the discovery of the ampulla of Vater.
• In 1761, Giovanni Morgagni described the clinical syndrome of severe upper abdominal pain, vomiting, and collapse (acute pancreatitis). He is also credited with the earliest pathological recognition of cancer of the pancreas.
• In 1842, Karl von Rokitansky, the premier pathologist of Vienna (Wiener Allgemeines Krankenhaus) was the first one to recognize acute hemorrhagic pancreatitis.
• In 1887, Rugero Oddi published his observations of the structure and function of the choledochal sphincter in Archives Italiennes de Biologie that laid the basis for understanding its role in pancreatic and biliary disease.
• In late 18th century, Reginald Fitz described 3 forms of acute pancreatitis (hemorrhagic, suppurative, and gangrenous) and proposed that fat necrosis was a sequel of severe pancreatitis
• In late 18th century, Nicholas Senn of Chicago, not only addressed the mechanisms of acute pancreatitis but also provided rational insight into the validity of surgical techniques for its treatment.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Joseph Nasr, M.D.[2]; Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[3]

Acute pancreatitis may be classified according to four complementary features: clinical phase, clinical severity, morphologic subtype, and type of pancreatic or peripancreatic collection. The Revised Atlanta Classification (RAC) is the principal international framework and classifies severity as mild, moderately severe, or severe according to organ failure and local or systemic complications.^[1] The Determinant-Based Classification (DBC) is an alternative four-tier system that combines organ failure with the presence and infection status of pancreatic or peripancreatic necrosis.^[2]

These classifications describe different aspects of the same episode and should not be used interchangeably. Etiologic classification, prediction scores such as APACHE II, BISAP, and the Ranson criteria, and imaging severity indices are addressed in their respective microchapters.

Classification axis	Categories	Principal clinical purpose
Clinical phase	Early phase and late phase	Distinguishes the predominantly systemic early response from the later course in which persistent organ failure and local complications must be described together
Clinical severity	Mild, moderately severe, or severe by the RAC; mild, moderate, severe, or critical by the DBC	Standardizes communication, outcome reporting, and clinical risk stratification
Morphology	Interstitial edematous pancreatitis or necrotizing pancreatitis	Describes the presence, location, and evolution of pancreatic or peripancreatic necrosis
Local collection	Acute peripancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection, or walled-off necrosis	Standardizes the description of collections according to pancreatitis subtype, contents, encapsulation, and time from symptom onset

Acute pancreatitis is classified below using the terminology and definitions of the Revised Atlanta Classification and the complementary Determinant-Based Classification.

Acute pancreatitis has two overlapping clinical phases: an early phase that usually lasts for the first week and a late phase that may continue for weeks to months.^[1][3][4]

Feature	Early phase	Late phase
Usual timing	First week after symptom onset	After the first week; may persist for weeks to months
Principal driver	Systemic response to pancreatic injury, including systemic inflammatory response syndrome and organ dysfunction	Persistent systemic inflammation, organ failure, and/or evolving local complications
Basis of severity assessment	Primarily clinical: presence and duration of organ failure	Clinical and morphologic: organ failure, local complications, and infection status
Role of imaging	Imaging may confirm an uncertain diagnosis or assess deterioration, but early CECT can underestimate evolving necrosis	Cross-sectional imaging is more reliable for characterizing necrosis, collection contents, and encapsulation
Patients affected	All patients with acute pancreatitis	Generally patients with moderately severe or severe acute pancreatitis

• The phases overlap rather than changing at a rigid time point.
• The onset of acute pancreatitis is dated from the onset of abdominal pain, not from hospital admission.^[1]
• Morphologic findings do not replace clinical assessment of organ failure in the early phase.
• Routine CT is not required solely to assign an early severity category when the diagnosis is established and the patient is improving. CT should be reserved for diagnostic uncertainty, clinical deterioration, or failure to improve after 48–72 hours.^[5]

Acute pancreatitis severity is classified most commonly using the three-tier Revised Atlanta Classification; the four-tier Determinant-Based Classification may be used when the interaction between organ failure and infected necrosis needs to be emphasized.

Acute pancreatitis is classified by the RAC as mild, moderately severe, or severe according to the presence and duration of organ failure and the presence of local or systemic complications.^[1][6][7]

RAC severity grade	Organ failure	Local or systemic complications	Definition
Mild	None	None	No organ failure and no local or systemic complications
Moderately severe	Transient organ failure that resolves within 48 hours, or no organ failure	May be present	Transient organ failure and/or local or systemic complications, without persistent organ failure
Severe	Persistent organ failure involving one or more organ systems	May be present or absent	Organ failure that persists beyond 48 hours

• Local complications include acute peripancreatic fluid collection, pancreatic pseudocyst, acute necrotic collection, walled-off necrosis, and other local manifestations such as gastric outlet dysfunction, splenic or portal vein thrombosis, and colonic necrosis.^[1]
• Systemic complications are exacerbations of pre-existing comorbid disease precipitated by acute pancreatitis, such as worsening chronic lung disease or coronary artery disease.^[1]
• Transient organ failure resolves within 48 hours and places the patient in the moderately severe category.
• Persistent organ failure continues beyond 48 hours and defines severe acute pancreatitis, whether it involves one organ system or multiple organ systems.^[8]
• Severity is dynamic. When organ failure is present but has not yet persisted for 48 hours, the episode should be considered potentially severe and reassessed rather than prematurely assigned a final category.^[1]
• Local complications alone do not define severe acute pancreatitis; severe disease requires persistent organ failure.

Acute pancreatitis is classified by the DBC according to two determinants: the systemic determinant of organ failure and the local determinant of pancreatic or peripancreatic necrosis and its infection status.^[2][9][10]

DBC severity grade	Local determinant	Systemic determinant	Definition
Mild	No pancreatic or peripancreatic necrosis	No organ failure	Neither determinant is present
Moderate	Sterile pancreatic or peripancreatic necrosis may be present	Transient organ failure may be present	Sterile necrosis and/or transient organ failure
Severe	Infected pancreatic or peripancreatic necrosis may be present	Persistent organ failure may be present	Infected necrosis or persistent organ failure, but not both together
Critical	Infected pancreatic or peripancreatic necrosis	Persistent organ failure	Both determinants are present

The principal distinction between the systems is that the DBC reserves a separate critical category for the combination of infected necrosis and persistent organ failure. Comparative cohort studies have found that both the RAC and DBC stratify worsening outcomes effectively; neither system has shown a consistent overall performance advantage, although the DBC provides additional separation of the highest-risk combination.^[11][12]

Acute pancreatitis was classified by the original 1992 Atlanta system as either mild or severe; the 2012 revision introduced a three-tier clinical severity system and standardized morphologic terminology.^[1][13]

Feature	Original Atlanta Classification (1992)	Revised Atlanta Classification (2012)
Severity categories	Mild and severe	Mild, moderately severe, and severe
Organ-failure definition	Heterogeneous clinical thresholds	Modified Marshall score ≥2 in the respiratory, renal, or cardiovascular system
Duration of organ failure	Not incorporated consistently	Transient if it resolves within 48 hours; persistent if it continues beyond 48 hours
Clinical phases	Not formally separated	Early and late phases
Morphologic subtypes	Terminology was less standardized	Interstitial edematous pancreatitis and necrotizing pancreatitis
Collection terminology	Included terms such as acute pseudocyst and pancreatic abscess	APFC, pseudocyst, ANC, and WON, defined by contents, encapsulation, pancreatitis subtype, and timing

The original Atlanta system used specific thresholds such as systolic blood pressure ≤90 mmHg, PaO₂ ≤60 mmHg, serum creatinine ≥2 mg/dL after rehydration, and gastrointestinal bleeding >500 mL in 24 hours as manifestations of organ failure. The RAC replaced these heterogeneous criteria with the standardized modified Marshall system.^[1][3]

Acute pancreatitis organ failure is defined by a modified Marshall score of 2 or more in at least one of three organ systems: respiratory, renal, or cardiovascular.^[1][14]

Organ system	Score 0	Score 1	Score 2	Score 3	Score 4
Respiratory: PaO2/FiO2	>400	301–400	201–300	101–200	≤100
Renal: serum creatinine, mg/dL	<1.4	1.4–1.8	1.9–3.6	3.7–4.9	>4.9
Cardiovascular: systolic blood pressure, mmHg	>90	<90, fluid responsive	<90, not fluid responsive	<90 with pH <7.3	<90 with pH <7.2

• A score of ≥2 in any one organ system defines organ failure.
• Organ failure may be single-organ or multiple-organ failure.
• In patients with pre-existing chronic kidney disease, the renal score must be interpreted according to deterioration from baseline because no formal correction exists for an elevated baseline creatinine.^[1]
• For a non-ventilated patient, estimated FiO₂ values are:
  • Room air: 0.21
  • 2 L/min supplemental oxygen: approximately 0.25
  • 4 L/min: approximately 0.30
  • 6–8 L/min: approximately 0.40
  • 9–10 L/min: approximately 0.50
• The modified Marshall score is used to define current organ failure. Prognostic scores estimate the risk of a future severe course and are not substitutes for the RAC severity definition.

Acute pancreatitis is divided into two morphologic subtypes: interstitial edematous pancreatitis and necrotizing pancreatitis.^[1][3][13]

Feature	Interstitial edematous pancreatitis	Necrotizing pancreatitis
Definition	Acute pancreatic and peripancreatic inflammation without recognizable tissue necrosis	Acute inflammation associated with necrosis of the pancreatic parenchyma, peripancreatic tissues, or both
Pancreatic enhancement on CECT	Relatively homogeneous enhancement	Nonenhancing pancreatic parenchyma when pancreatic necrosis is present; the gland may enhance normally in isolated peripancreatic necrosis
Peripancreatic findings	Fat haziness or stranding; an acute peripancreatic fluid collection may be present	Heterogeneous areas or collections containing variable amounts of necrotic tissue and fluid
Anatomic patterns	No necrosis	Combined pancreatic and peripancreatic necrosis is most common; isolated peripancreatic necrosis is less common; isolated pancreatic parenchymal necrosis is rare
Possible evolution	Resolution, APFC, or pseudocyst	Sterile or infected necrosis; ANC or WON

• Interstitial edematous pancreatitis is the most common morphologic subtype and usually resolves during the first week.^[1]
• Necrotizing pancreatitis occurs in approximately 5–10% of patients.^[1][5]
• Early CECT may show patchy or heterogeneous enhancement before necrosis becomes clearly demarcated. When imaging is clinically indicated, a nonenhancing area after the first week is considered pancreatic parenchymal necrosis.^[1][15]
• Pancreatic necrosis is defined by nonviable pancreatic parenchyma and/or peripancreatic tissue, not by a mandatory threshold of more than 3 cm or more than 30% of the gland.
• The extent of necrosis does not have an absolute relationship with the risk of infection.^[1]
• Morphologic subtype and clinical severity are separate axes. Necrotizing pancreatitis may occur without persistent organ failure, while persistent organ failure defines severe acute pancreatitis regardless of the morphologic subtype.

Acute pancreatitis collections are classified according to the underlying morphologic subtype, the presence or absence of necrotic material, encapsulation, and time from symptom onset.^[1][16]

Collection	Associated morphology	Usual timing	Contents	Wall and location
Acute peripancreatic fluid collection (APFC)	Interstitial edematous pancreatitis	Within the first 4 weeks	Homogeneous fluid without a nonliquid component	No definable wall; confined by normal peripancreatic fascial planes; adjacent to the pancreas without intrapancreatic extension
Pancreatic pseudocyst	Interstitial edematous pancreatitis	Usually more than 4 weeks	Homogeneous fluid with no solid necrotic component	Well-defined, completely encapsulated inflammatory wall; usually outside the pancreas
Acute necrotic collection (ANC)	Necrotizing pancreatitis	Within the first 4 weeks	Variable amounts of fluid and necrotic tissue; may appear relatively homogeneous early	No definable wall; may be intrapancreatic and/or extrapancreatic
Walled-off necrosis (WON)	Necrotizing pancreatitis	Usually 4 weeks or more	Encapsulated pancreatic and/or peripancreatic necrotic material with variable fluid content	Mature, well-defined inflammatory wall; may be intrapancreatic and/or extrapancreatic

• The 4-week threshold describes the usual evolution of a collection and should be interpreted with its contents and degree of encapsulation rather than used in isolation.
• Within the first week, APFC and ANC may both appear predominantly fluid and may be difficult to distinguish. Sequential CT, MRI, ultrasound, or endoscopic ultrasound may better demonstrate a solid necrotic component.^[1]
• A true pseudocyst contains fluid without necrotic debris. A mature collection containing necrotic material is WON, even if it appears predominantly cystic on CT.^[13]
• WON usually matures after approximately 4 weeks, although demarcated necrotic collections may occasionally form earlier.^[17]
• Infection is a modifier rather than a separate collection type. Necrosis and collections should be described as sterile or infected when this is known or strongly suspected.
• Extraluminal gas within pancreatic or peripancreatic necrosis strongly suggests infection, but the absence of gas does not exclude infected necrosis.^[1][12]

Acute pancreatitis should be reported using standardized RAC terminology so that the clinical severity grade, morphologic subtype, and collection type remain distinct.

Avoid or qualify	Preferred terminology	Reason
Acute pseudocyst	APFC or ANC, depending on contents and morphologic subtype	A pseudocyst is an encapsulated fluid-only collection that usually requires more than 4 weeks to mature
Pancreatic abscess	Infected ANC or infected WON	The older term does not adequately describe whether necrotic material or a mature wall is present
Phlegmon	Describe the specific inflammatory change, necrosis, or collection	The term is nonspecific and is not part of the RAC lexicon
Organized pancreatic necrosis or necroma	WON	WON is the standardized term for mature encapsulated necrosis
Severe pancreatitis based on CT appearance alone	State the morphologic subtype and assign RAC severity according to organ failure	Persistent organ failure, not the extent of imaging abnormalities alone, defines severe acute pancreatitis

A complete description should include:

• Time from onset of abdominal pain
• RAC severity category and whether organ failure is transient or persistent
• Organ system or systems involved
• Interstitial edematous or necrotizing morphology
• Location of necrosis: pancreatic, peripancreatic, or both
• Collection type, location, contents, and degree of encapsulation
• Sterile or infected status when known or strongly suspected
• Relevant additional local complications

Acute pancreatitis classification is dynamic and must be updated as organ failure resolves or persists and as local complications evolve.

High-yield principles

• The duration of organ failure is the key distinction between moderately severe and severe acute pancreatitis.
• A modified Marshall score of ≥2 in any assessed organ system defines organ failure; persistence beyond 48 hours defines severe acute pancreatitis.
• Mild acute pancreatitis requires all three of the following: no organ failure, no local complications, and no systemic complications.
• A local complication without persistent organ failure is classified as moderately severe, not severe.
• Morphologic subtype, collection type, and clinical severity should each be stated separately.
• The DBC adds a critical category for infected necrosis combined with persistent organ failure.

Common pitfalls

• Assigning a final severity category at admission when the duration of organ failure is not yet known
• Omitting systemic complications from the definition of moderately severe acute pancreatitis
• Treating a prognostic score as though it were the RAC severity classification
• Equating necrotizing pancreatitis with severe acute pancreatitis
• Defining pancreatic necrosis by an obsolete size or percentage threshold
• Calling every mature pancreatic collection a pseudocyst without assessing for solid necrotic debris
• Applying the 4-week threshold without considering collection contents and encapsulation
• Using early CECT to exclude necrosis when perfusion abnormalities have not yet fully evolved

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Joseph Nasr, M.D.[2]; Monish Thuvooru Muthu Kalyanaraman, M.B.B.S[3]

Acute pancreatitis (AP) is an acute inflammatory injury of the pancreas in which an initiating insult disrupts acinar and ductal cell homeostasis. Premature digestive-enzyme activation, sustained intracellular calcium elevation, mitochondrial failure, impaired autophagy, lipotoxicity, and regulated cell-death pathways interact to produce local pancreatic injury.^[1][2] Release of damage-associated molecular patterns, activated enzymes, cytokines, and lipotoxic metabolites then recruits innate immune cells and may progress to endothelial dysfunction, capillary leak, pancreatic microcirculatory failure, systemic inflammatory response syndrome, and organ failure.

Pathophysiologic level	Principal abnormalities	Major consequences
Acinar cell	Premature zymogen activation, sustained Ca2+ signaling, mitochondrial permeability transition, impaired autophagy, and ER stress	ATP depletion, intracellular enzyme activation, necrosis, and release of inflammatory mediators
Ductal cell	Impaired CFTR-mediated bicarbonate and fluid secretion	Acidic, low-volume ductal secretions, protein plugging, impaired washout, and enhanced intraductal enzyme activation
Stellate and immune cells	Ca2+-dependent intercellular signaling, macrophage and neutrophil activation, inflammasome signaling, and complement activation	Amplification of acinar injury and local inflammation
Adipose tissue and circulating triglycerides	Pancreatic lipase-mediated release of nonesterified unsaturated fatty acids	Mitochondrial toxicity, endothelial injury, fat necrosis, and systemic organ injury
Systemic circulation	DAMPs, cytokines, activated leukocytes, endothelial activation, capillary leak, and microthrombosis	SIRS, acute respiratory failure, acute kidney injury, shock, and multiorgan failure

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][3] 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.^[2][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][2][9][10]}

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 injury is increasingly recognized as a key early event that may precede both cytokine release and trypsinogen activation.^[11] The principal manifestation is persistent opening of the MPTP, a cyclophilin D (CypD)-dependent solute channel, which causes:^[12]

• 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.^[13]

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.^[14]

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.^[15] This mechanism also explains the clinical association between CFTR mutations and recurrent AP.^[12][16][17]

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.^[18][19][20]

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.^{[21][22][23][24]}

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:^[25][26]

Cell-death pathway	Principal mechanism	Pathophysiologic consequence
Apoptosis	Caspase-dependent, energy-requiring programmed cell death	Relatively contained removal of injured cells with limited release of intracellular DAMPs; generally associated with less severe inflammation than necrotic cell death
Necroptosis	Regulated necrosis mediated by the RIP1/RIP3/MLKL necrosome complex after TNF, Fas-ligand, or TLR signaling	Membrane disruption and DAMP release, with activation of NLRP3 inflammasomes and amplification of inflammation
Pyroptosis	Inflammasome-dependent, gasdermin-mediated inflammatory cell death	Release of inflammatory intracellular contents and cytokines
Ferroptosis	Iron-dependent lipid peroxidation and membrane injury	Increasingly implicated in intestinal epithelial and barrier injury during severe acute pancreatitis

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.^[27] Interventions that shift the balance from necrosis toward apoptosis (e.g., XIAP inhibition, RIP3 deletion, necrostatin treatment) consistently reduce disease severity in experimental models.

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.^[28][29] 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.^[30][31]

Alcohol-induced pancreatitis involves both oxidative and nonoxidative metabolic pathways within acinar cells.^[32] 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.^[33] 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.^[34][23][24]

Drug-induced pancreatitis is uncommon and may occur through 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.^[1][35]

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.^[36][8]

The transition from localized pancreatic injury to systemic disease follows a well-characterized inflammatory cascade:^[37][38]

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.^[39][2] 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.^[40]
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.^[41][42]
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.^[43][44]
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.^[45][46]

Organ failure in AP follows a biphasic pattern with distinct pathophysiology and clinical implications:^[24][47]

Phase	Typical timing	Dominant mechanism
Early or primary organ failure	Usually within the first 1–2 weeks	Sterile SIRS generated by the initial pancreatic and systemic inflammatory insult; occurs in approximately 20% of patients and carries substantial early mortality
Late or secondary organ failure	After the initial inflammatory phase	Sepsis associated with infected pancreatic necrosis, often after compensatory anti-inflammatory response syndrome characterized by HLA-DR suppression, increased co-inhibitory signaling, impaired host defense, and greater susceptibility to 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.^[48][49][50]

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.^[24]

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.^[51] 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.^[24] 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.

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 pancreatic necrosis correlates with disease severity. Necrosis is initially sterile but may later become infected through bacterial translocation, transforming the clinical course from sterile SIRS-driven disease to sepsis-driven disease.

The following targets arise directly from the cellular pathways described above. Most evidence remains preclinical, and none should be interpreted as established disease-specific therapy.

• Calcium and mitochondrial pathways: Investigational targets include 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.^[52] 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.^[53] 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.^[54]
• CFTR restoration and other pathway-directed approaches: 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.^[55][56] 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.^[57]

• 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
• 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

Genetic susceptibility to acute pancreatitis involves variants that alter trypsin activation or degradation, ductal bicarbonate secretion, calcium homeostasis, protein folding, and endoplasmic-reticulum stress. The best-characterized variants include:

Gene	Normal role	Pathogenic mechanism
PRSS1	Encodes cationic trypsinogen	Gain-of-function variants such as R122H and N29I promote premature autoactivation or resistance to degradation; the prototypical autosomal-dominant cause of hereditary pancreatitis
SPINK1	Inhibits prematurely activated trypsin	Loss-of-function variants such as N34S reduce intrapancreatic trypsin inhibition and usually act as disease modifiers
CTRC	Degrades trypsinogen and trypsin	Reduced protective degradation increases intrapancreatic trypsin activity and modifies susceptibility and progression
CFTR	Supports ductal chloride, bicarbonate, and fluid secretion	Impaired ductal secretion increases protein concentration and intraductal calcium and promotes obstruction and enzyme activation; co-inheritance with SPINK1 may further increase risk
CPA1	Encodes carboxypeptidase A1	Misfolding variants produce endoplasmic-reticulum stress
CLDN2	Encodes the X-linked tight-junction protein claudin-2	Variants are associated with alcohol- and smoking-related pancreatitis susceptibility
CASR	Regulates extracellular and intracellular calcium responses	Variants may alter calcium homeostasis and modify susceptibility to pancreatitis

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).^[58][59]

Acute pancreatitis is associated with several disorders or exposures that converge on the same cellular pathways but enter through different initiating mechanisms.

Associated condition or exposure	Pathophysiologic relationship
Biliary stone disease	Transient ampullary or pancreatic duct obstruction increases ductal pressure and exposes acinar and ductal cells to bile-acid signaling, promoting pathologic Ca2+ release and enzyme activation.[29]
Alcohol use and cigarette smoking	Oxidative and nonoxidative alcohol metabolites impair mitochondrial function, calcium clearance, autophagy, and CFTR-mediated ductal secretion; smoking may amplify ER stress and acinar-cell injury.[32]
Hypertriglyceridemia, obesity, and visceral adiposity	Lipolysis generates toxic nonesterified fatty acids that injure acinar cells, mitochondria, endothelium, renal tubules, and pulmonary tissue.[34][21]
Cystic fibrosis and CFTR-related disease	Reduced ductal bicarbonate and fluid secretion produces concentrated, acidic secretions and impaired zymogen washout, increasing susceptibility to acute or recurrent pancreatitis.[15]
Hereditary or recurrent pancreatitis	Variants in PRSS1, SPINK1, CTRC, CPA1, CFTR, CASR, and related genes alter trypsin regulation, ductal secretion, protein folding, or calcium homeostasis.[25]
ERCP and pancreatic duct instrumentation	Mechanical, hydrostatic, chemical, and thermal injury may disrupt ductal and acinar homeostasis and activate calcineurin and NF-κB signaling.[36]
Drug exposure and metabolic abnormalities	Mechanisms vary and may include direct acinar toxicity, immune-mediated injury, hypertriglyceridemia, or hypercalcemia rather than one shared drug-specific pathway.[1]

On gross examination, acute pancreatitis ranges from interstitial edematous inflammation to necrotizing and hemorrhagic injury.^[1][60]

Gross pattern	Findings
Interstitial edematous pancreatitis	Diffuse or focal pancreatic enlargement Interstitial edema and congestion Peripancreatic inflammatory change No macroscopic pancreatic parenchymal necrosis
Necrotizing pancreatitis	Nonviable pancreatic parenchyma and/or peripancreatic tissue Irregular gray-white or yellow necrotic tissue Peripancreatic fat necrosis Acute necrotic collections that may later become organized or walled off
Hemorrhagic injury	Dark red-black discoloration Parenchymal and peripancreatic hemorrhage Vascular erosion or thrombosis in severe disease
Fat necrosis	Chalky white deposits caused by calcium soap formation Involvement of peripancreatic, mesenteric, or omental fat

On microscopic examination, acute pancreatitis is characterized by variable combinations of interstitial edema, acute inflammation, acinar-cell injury, fat necrosis, hemorrhage, and vascular damage.^[1][3]

Microscopic feature	Histopathologic appearance and significance
Interstitial edema	Separation of acinar lobules by protein-rich fluid, often with vascular congestion and early inflammatory infiltrates
Acinar-cell injury and necrosis	Cytoplasmic vacuolization, loss of normal acinar architecture, nuclear pyknosis or karyolysis, and coagulative or liquefactive necrosis
Acute inflammation	Predominantly neutrophilic infiltration of pancreatic and peripancreatic tissue, with macrophage recruitment and inflammatory debris
Fat necrosis and saponification	Ghost outlines of adipocytes, basophilic granular calcium deposits, and surrounding inflammation
Hemorrhage and vascular injury	Extravasated erythrocytes, endothelial injury, fibrin deposition, microvascular thrombosis, and occasional vessel-wall necrosis
Infected necrosis	Necrotic tissue with microorganisms and suppurative inflammation; this is a secondary complication rather than a defining feature of early sterile pancreatitis

• Electron microscopy is not required for routine diagnosis.
• Experimental ultrastructural findings include swollen mitochondria with disrupted cristae, dilated endoplasmic reticulum, abnormal zymogen-lysosome colocalization, and enlarged autolysosomal vacuoles.^[14][12]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]

Acute pancreatitis may be either idiopathic or caused by alcohol, gallstones, trauma, steroids, mumps, autoimmune diseases, ERCP, hypercalcemia, hyperlipidemia, hypertriglyceridemia or certain medications. Gallstones are the most common cause of acute pancreatitis, followed by chronic alcohol consumption (4-5 drinks daily for ~5 years). There are numerous primary and secondary causes of acute pancreatitis that must be considered in a patient’s work up.

Gallstones are the most common cause of acute pancreatitis, followed by chronic alcohol consumption (4-5 drinks daily for ~5 years).^[1] However; there are numerous primary and secondary causes of acute pancreatitis that must be considered in a patient’s work up.^[2]

The following table summarizes the most common causes of acute pancreatitis:^[3]

Cause	Frequency	Comment
Gallstones	40%	Gallstones or sludge
Alcohol	30%	4-5 drinks daily for 5 years
Hypertriglyceridemia	2-5%	>1000 mg/dL
Genetic	unknown	Causing recurrent acute or chronic pancreatitis
Drug-induced	<5%	Most commonly azathioprine, 6-mercaptopurine, didanosine, valproic acid, ACEi, mesalamine
Autoimmune	<1%	Presents as Type I or Type II
ERCP (Iatrogenic)	5-10% of procedures	Treated with rectal NSAIDs or temporary pancreatic duct stent placement
Trauma	Blunt force trauma to the mid-abodmen	Blunt force trauma to the mid-abdomen
Infection	<1%	Primarily caused by CMV, mumps, or EBV. May be caused by ascaris or clonorchis
Surgical	5-10% of patients on cardiopulmonary bypass	–
Obstruction	Rare	Caused by celiac disease, crohn’s disease, and perpetrated by pancreas divisium or sphincter of Oddi dysfunction

Sphincter of Oddi dysfunction and pancreas divisium have been traditionally associated with the development of acute pancreatitis; however, recent data suggests otherwise.^[4] Pancreas divisium has been associated with genetic mutations that may be the true underlying cause of pancreatitis. Alternatively, the presence of the abnormal anatomy alone may not predispose patients to acute pancreatitis; however, in lieu of a genetic mutation may superimpose on the existing anatomical variation to contribute in the pathogenesis of acute pancreatitis.^[5][6]

Chronic alcoholism and smoking have been associated with the development of acute pancreatitis. Though alcohol has been proposed to be pathogenic in combination with the presence of an underlying genetic mutation. Alcoholism causing pancreatitis is more common in males than females. This may be due to the propensity of males to consume alcohol more than females, or due to the genetic mutations occurring more commonly in males.^[7][8]

Common iatrogenic causes of pancreatitis include ERCP procedures as well as use of medication. Hundreds of medications have been implicated in causing pancreatitis; however, the most common drugs include:^[9][10]

• Steroid use
• Azathioprine
• 6-Mercaptopurine
• Didanosine
• Valproic acid
• Angiotensin Converting Enzyme inhibitors (ACEi)
• Mesalamine

It is extremely difficult to identify a particular drug which may be responsible for the development of pancreatitis as there are usually multiple possibilities to the underlying etiology of the pancreatitis in patients with comorbidities; however, patients hospitalized for acute pancreatitis are often found to be using one or more drugs associated with the development of the disease.^[11][12]

Several genes have been proposed to play a role in the pathogenesis of acute pancreatitis. While the exact role of every implicated genetic mutation is not fully understood, the following genes have been associated with the development of acute pancreatitis:^[13][14]

• CFTR
• PRSS-1
• SPINK-1
• Chymotrypsin C
• Claudin-2
• Calcium sensing receptors

A common mnemonic for the causes of pancreatitis spells “I get smashed”, an allusion to heavy drinking (one of the many causes):

• I – idiopathic
• G – gallstone. Gallstones that travel down the common bile duct and which subsequently get stuck in the ampulla of vater can cause obstruction in the outflow of pancreatic juices from the pancreas into the duodenum. The back-flow of these digestive juices causes lysis (dissolving) of pancreatic cells and subsequent pancreatitis.
• E – ethanol (alcohol) – Alcohol has been proposed to cause acute pancreatitis in combination with genetic factors. It is more commonly a cause in males than females. This may be due to the propensity of males to chronically abuse alcohol, or by genetic factors more commonly present in males.
• T – trauma
• S – steroids – Commonly used in patients with autoimmune diseases. Type I presents with obstructive jaundice and elevated IgG4 levels. Type II presents in younger patients with no increase in IgG4 levels.
• M – mumps (paramyxovirus) and other viruses (Epstein-Barr virus, Cytomegalovirus)
• A – autoimmune disease (Polyarteritis nodosa, Systemic lupus erythematosus)
• S – scorpion sting – Tityus Trinitatis – Trinidad/ snake bite
• H – hypercalcemia, hyperlipidemia/hypertriglyceridemia and hypothermia
• E – ERCP (Endoscopic Retrograde Cholangio-Pancreatography – a procedure that combines endoscopy and fluoroscopy)
• D – drugs (SAND – steroids & sulfonamides, azathioprine, NSAIDS, diuretics such as furosemide and thiazides, & didanosine) and duodenal ulcers. Drugs often present with mild pancreatitis and rarely are associated with signs of drug allergy such as rash.

Cardiovascular	Cholesterol embolism, Polyarteritis nodosa
Chemical / poisoning	Scorpion sting, Snake bite, Zinc, Ethanol
Dermatologic	No underlying causes
Drug Side Effect	Asparaginase, Azathioprine, Bexarotene, Bumetanide, Didanosine, Diuretics, Enfuvirtide, Ethanol, Exenatide, Frusemide, Isotretinoin, Linagliptin, Liraglutide, Mesalazine, Metronidazole, NSAIDS, Olsalazine, Oxyphenbutazone, Pentamidine, Sitagliptin, Steroids, Sulfonamides, Thiazide, Valproic acid
Ear Nose Throat	No underlying causes
Endocrine	Primary hyperparathyroidism
Environmental	No underlying causes
Gastroenterologic	Bile duct cysts,Cholangiocarcinoma, Choledochal cyst, Choledocholithiasis, Cholelithiasis, Duodenal ulcer, Gallstones , Gastric ulcer, Long common duct, Pancreas divisum, Pancreas duct obstruction, Pancreatic abnormalities, Pancreatic cancer, Pancreatic cysts , Peptic ulcer , Reye syndrome, Hereditary pancreatitis, Cystic fibrosis
Genetic	Apolipoprotein C-II deficiency, Cystic fibrosis, Familial hypertriglyceridaemia, Familial partial lipodystrophy type 1 , Hereditary pancreatitis, Lipoprotein lipase deficiency
Hematologic	No underlying causes
Iatrogenic	Abdominal surgery , Endoscopic retrograde cholangiopancreatography, Ischemia from bypass surgery, Reye’s syndrome
Infectious Disease	Ascaris blocking pancreatic outflow, Campylobacter jejuni, Chinese liver fluke, Coxsackie B virus, Cytomegalovirus, Epstein-Barr virus , HIV-1 disease, Human enterovirus B, Varicella zoster, Mumps, Mycoplasma pneumoniae, Teniasis, Varicella-zoster virus
Musculoskeletal / Ortho	No underlying causes
Neurologic	No underlying causes
Nutritional / Metabolic	Hypercalcaemia, Hyperlipidemia, Hypertriglyceridemia, Lipoprotein lipase deficiency, Apolipoprotein C-II deficiency, Familial hypertriglyceridaemia, Familial partial lipodystrophy type 1
Obstetric/Gynecologic	No underlying causes
Oncologic	Cholangiocarcinoma, Pancreatic cancer
Opthalmologic	No underlying causes
Overdose / Toxicity	Asparaginase, Azathioprine, Bexarotene, Bumetanide, Didanosine, Diuretics, Enfuvirtide, Ethanol, Exenatide, Frusemide, Linagliptin, Liraglutide, Mesalazine, Metronidazole, NSAIDS, Olsalazine, Oxyphenbutazone, Sitagliptin, Steroids, Sulfonamides, Thiazide, Valproic acid
Psychiatric	No underlying causes
Pulmonary	Cystic fibrosis
Renal / Electrolyte	No underlying causes
Rheum / Immune / Allergy	Autoimmune disease , Polyarteritis nodosa, Sytemic lupus erythematosus
Sexual	Cystic fibrosis
Trauma	Abdominal trauma , Pancreatic trauma
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Excessive alcohol, Hypothermia, Idiopathic, Repeated marathon running

Abdominal surgery Abdominal trauma Apolipoprotein C-II deficiency Ascaris blocking pancreatic outflow Asparaginase Autoimmune diseases Azathioprine Bexarotene Bile duct cysts Bumetanide Campylobacter jejuni Chinese liver fluke Cholangiocarcinoma Choledochal cyst Choledocholithiasis Cholelithiasis Cholesterol embolism Coxsackie B virus Cystic fibrosis Cytomegalovirus Didanosine Diuretics Duodenal ulcer Endoscopic retrograde cholangiopancreatography Enfuvirtide Epstein-Barr virus Ethanol Excessive alcohol Exenatide_JAMA_Internal_Medicine_|_Glucagonlike_Peptide_1–Based_Therapies_and_Risk_of_Hospitalization_for_Acute_Pancreatitis_in_Type_2_Diabetes_MellitusA_Population-Based_Matched_Case-Control_StudyGLP-1_and_the_Risk_of_Acute_Pancreatitis-15|[15] Familial hypertriglyceridaemia Familial partial lipodystrophy type 1 Frusemide Gallstones Gastric ulcer Hereditary pancreatitis HIV-1 disease Human enterovirus B Hypercalcaemia

Hyperlipidemia Hypertriglyceridemia Hypothermia Idiopathic Ischemia from bypass surgery Isotretinoin Linagliptin Lipoprotein lipase deficiency Liraglutide Long common duct Mesalazine Metronidazole Mumps Mycoplasma pneumoniae NSAIDS Olsalazine Oxyphenbutazone Pancreas divisum Pancreas duct obstruction Pancreatic abnormalities Pancreatic cancer Pancreatic cysts Pancreatic trauma Peptic ulcer Polyarteritis nodosa Primary hyperparathyroidism Repeated marathon running Reye syndrome Scorpion sting Sitagliptin_JAMA_Internal_Medicine_|_Glucagonlike_Peptide_1–Based_Therapies_and_Risk_of_Hospitalization_for_Acute_Pancreatitis_in_Type_2_Diabetes_MellitusA_Population-Based_Matched_Case-Control_StudyGLP-1_and_the_Risk_of_Acute_Pancreatitis-15|[15] Snake bite Steroids Sulfonamides Systemic lupus erythematosus Teniasis Thiazide Valproic acid Varicella-zoster virus Zinc

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]; Tarek Nafee, M.D. [3]; Iqra Qamar M.D.[4]

Acute pancreatitis must be differentiated from gallstones, pancreatic cysts, pancreatic pseudocysts, and chronic pancreatitis.

The following table outlines the major differential diagnoses of abdominal pain.

Abbreviations: RUQ= Right upper quadrant of the abdomen, LUQ= Left upper quadrant, LLQ= Left lower quadrant, RLQ= Right lower quadrant, LFT= Liver function test, SIRS= Systemic inflammatory response syndrome, ERCP= Endoscopic retrograde cholangiopancreatography, IV= Intravenous, N= Normal, AMA= Anti mitochondrial antibodies, LDH= Lactate dehydrogenase, GI= Gastrointestinal, CXR= Chest X ray, IgA= Immunoglobulin A, IgG= Immunoglobulin G, IgM= Immunoglobulin M, CT= Computed tomography, PMN= Polymorphonuclear cells, ESR= Erythrocyte sedimentation rate, CRP= C-reactive protein, TS= Transferrin saturation, SF= Serum Ferritin, SMA= Superior mesenteric artery, SMV= Superior mesenteric vein, ECG= Electrocardiogram, US = Ultrasound

Classification of pain in the abdomen based on etiology Disease Clinical manifestations Diagnosis Comments Symptoms Signs Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Abdominal causes Inflammatory causes Pancreato-biliary disorders Acute suppurative cholangitis RUQ + + + + − − − − + + + N Abnormal LFT WBC >10,000 Ultrasound shows biliary dilatation/stents/tumor Septic shock occurs with features of SIRS Acute cholangitis RUQ + − − + − − − − − − − N Abnormal LFT Ultrasound shows biliary dilatation/stents/tumor Biliary drainage (ERCP) + IV antibiotics Acute cholecystitis RUQ + − + + − − − − − − − Hypoactive Hyperbilirubinemia Leukocytosis Ultrasound shows: Gallstone Inflammation Murphy’s sign Acute pancreatitis Epigastric + − + ± − − + − ± − − N Increased amylase / lipase Ultrasound shows evidence of inflammation CT scan shows severity of pancreatitis Pain radiation to back Chronic pancreatitis Epigastric − − ± ± − + + − − − − N Increased amylase / lipase Increased stool fat content Pancreatic function test CT scan Calcification Pseudocyst Dilation of main pancreatic duct Predisposes to pancreatic cancer Pancreatic carcinoma Epigastric − − + + − + + − − − − N ↑ Alkaline phosphatase ↑ serum bilirubin ↑ gamma-glutamyl transpeptidase ↑ CA 19-9  MDCT with  PET/CT MRI Skin manifestations may include: Bullous pemphigoid Cicatricial pemphigoid Migratory superficial thrombophlebitis (classic Trousseau’s syndrome) Pancreatic panniculitis Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Primary biliary cirrhosis RUQ/Epigastric − − − + − − − − − − − N Increased AMA level, abnormal LFTs ERCP Pruritis Primary sclerosing cholangitis RUQ + − − + − − − − − − − N Increased liver enzymes Increased IgM, IgG4 Anti-neutrophil cytoplasmic antibody (p-ANCA) Anti-nuclear antibody (ANA) Anti-smooth muscle antibody (Anti-Sm) Anti-endothelial antibody Anti-cardiolipin antibody ERCP and MRCP shows Multiple segmental strictures Mural irregularities Biliary dilatation and diverticula Distortion of biliary tree The risk of cholangiocarcinoma in patients with primary sclerosing cholangitis is 400 times higher than the risk in the general population. Cholelithiasis RUQ/Epigastric ± − ± ± − − − − − − − Normal to hyperactive for dislodged stone Leukocytosis Ultrasound shows gallstone Fatty food intolerance Gastric causes Peptic ulcer disease Diffuse ± − + − − − + Gastric ulcer- melena and hematemesis Duodenal ulcer- melena and hematochezia Positive if perforated Positive if perforated Positive if perforated N Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl Air under diaphragm in upright CXR Upper GI endoscopy for diagnosis Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Gastritis Epigastric ± − + − − − Positive in chronic gastritis + − − − N H.pylori infection diagnostic tests Endoscopy H.pylori gastritis guideline recommendation Gastroesophageal reflux disease Epigastric − − ± − − − − − − − − N N Gastric emptying studies Esophageal manometry Endoscopy for alarm signs Gastric outlet obstruction Epigastric − − ± − − − + − − − − Hyperactive Complete blood count Basic metabolic panel Abdominal x-ray– air fluid level Barium upper GI studies– narrowed pylorus Succussion splash Gastroparesis Epigastric − − + − − − + − ± − − Hyperactive/hypoactive Hemoglobin Fasting plasma glucose Serum total protein, albumin, thyrotropin (TSH), and an antinuclear antibody (ANA) titer HbA1c Scintigraphic gastric emptying Succussion splash Single photon emission computed tomography (SPECT) Full thickness gastric and small intestinal biopsy Gastrointestinal perforation Diffuse + ± – ± − − − + + + ± Hyperactive/hypoactive WBC> 10,000 Air under diaphragm in upright CXR Hamman’s sign Dumping syndrome Lower and then diffuse − − + − − + + − + − − Hyperactive Glucose challenge test Hydrogen breath test Upper GI series Gastric emptying study Postgastrectomy Intestinal causes Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Acute appendicitis Starts in epigastrium, migrates to RLQ + Positive in pyogenic appendicitis + − − ± − − Positive in perforated appendicitis + + Hypoactive Leukocytosis Ct scan Ultrasound Positive Rovsing sign Positive Obturator sign Positive Iliopsoas sign Acute diverticulitis LLQ + ± + − + ± − + Positive in perforated diverticulitis + + Hypoactive Leukocytosis CT scan Ultrasound History of constipation Inflammatory bowel disease Diffuse ± − − ± − + + + − − − Normal or hyperactive Anti-neutrophil cytoplasmic antibody (P-ANCA) in Ulcerative colitis Anti saccharomyces cerevisiae antibodies (ASCA) in Crohn’s disease String sign on abdominal x-ray in Crohn’s disease Extra intestinal findings: Uveitis Arthritis Irritable bowel syndrome Diffuse − − − − ± ± + − − − − N Normal Normal Symptomatic treatment High dietary fiber Osmotic laxatives Antispasmodic drugs Whipple’s disease Diffuse ± − − ± − + + − ± − − N Thrombocytopenia Hypoalbuminemia Small intestinal biopsy for Tropheryma whipplei Endoscopy is used to confirm diagnosis. Images used to find complications Chest and joint x-ray CT MRI Echocardiography Extra intestinal findings: Uveitis Endocarditis Encephalitis Dementia Hepatosplenomegaly Arthritis Ascites Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Toxic megacolon Diffuse + − − − − + − − + ± + Hypoactive Anemia Leukocytosis especially in patients with Clostridium difficile infection Hypoalbuminemia Metabolic alkalosis associated with a poor prognosis Metabolic acidosis secondary to ischemic colitis CT and Ultrasound shows: Loss of colonic haustration Hypoechoic and thickened bowel walls with irregular internal margins in the sigmoid and descending colon Prominent dilation of the transverse colon (>6 cm) Insignificant dilation of ileal bowel loops (diameter >18 mm) with increased intraluminal gas and fluid Tropical sprue Diffuse + − − − − + + − − − − N Fat soluble vitamin deficiency Hypoalbuminemia Fecal stool test Barium studies: Dilation and edema of mucosal folds Steatorrhea– 10-40 g/day (Normal=5 g/day) Celiac disease Diffuse − − − − − + + − − − − Hyperactive IgA endomysial antibody IgA tissue transglutaminase antibody Anti-gliadin antibody Small bowel biopsy US: Bull’s eye or target pattern Pseudokidney sign Gluten allergy Infective colitis Diffuse + − ± − − + − + Positive in fulminant colitis ± ± Hyperactive Stool culture and studies Shiga toxin in bloody diarrhea PCR CT scan Bowel wall thickening Edema Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Colon carcinoma Diffuse/ RLQ/LLQ − − − − ± ± + + ± − − Normal or hyperactive if obstruction present CBC Carcinoembryonic antigen (CEA) Colonoscopy Flexible sigmoidoscopy Barium enema CT colonography  PILLCAM 2: A colon capsule for CRC screening may be used in patients with an incomplete colonoscopy who lacks obstruction Hepatic causes Viral hepatitis RUQ + − + + − Positive in Hep A and E + − Positive in fulminant hepatitis Positive in acute + N Abnormal LFTs Viral serology US Hep A and E have fecal-oral route of transmission Hep B and C transmits via blood transfusion and sexual contact. Liver abscess RUQ + + + + − ± + − + + ± Normal or hypoactive CBC Blood cultures Abnormal liver function tests US CT Hepatocellular carcinoma/Metastasis RUQ + − − + − − + − − − − Normal Hyperactive if obstruction present High levels of AFP in serum Abnormal liver function tests US CT Liver biopsy Other symptoms: Splenomegaly Variceal bleeding Ascites Spider nevi Asterixis Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Budd-Chiari syndrome RUQ ± − − ± − − − Positive in liver failure leading to varices − − − N Elevated serum aspartate aminotransferase and alanine aminotransferase levels may be more than five times the upper limit of the normal range. Elevated serum alkaline phosphatase and bilirubin levels, decreased serum albumin level. Findings on CT scan suggestive of Budd-Chiari syndrome include: Early enhancement of the caudate lobe and central liver around the inferior vena cava Delayed enhancement of the peripheral liver with accompanying central low density (flip-flop appearance) Peripheral zones of the liver show reversed portal venous blood flow In the chronic phase, there is caudate lobe enlargement and atrophy of the peripheral liver in affected areas Ascitic fluid examination shows: Total protein more than 2.5 g per deciliter White blood cells are usually less than 500/μL. Hemochromatosis RUQ − − − − − − − Positive in cirrhotic patients − − − N >60% TS >240 μg/L SF Raised LFT Hyperglycemia Ultrasound shows evidence of cirrhosis Extra intestinal findings: Hyperpigmentation Diabetes mellitus Arthralgia Impotence in males Cardiomyopathy Atherosclerosis Hypopituitarism Hypothyroidism Extrahepatic cancer Prone to specific infections Cirrhosis RUQ − − − + − − + + + − − N Hypoalbuminemia Prolonged PT Abnormal LFTs Hyponatremia Thrombocytopenia US Nodular, shrunken liver Ascites Stigmata of liver disease Cruveilhier- Baumgarten murmur Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Peritoneal causes Spontaneous bacterial peritonitis Diffuse + − − Positive in cirrhotic patients − + − − ± + + Hypoactive Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism Ultrasound for evaluation of liver cirrhosis Renal causes Pyelonephritis Unilateral + ± + − − − − − + − − Hypoactive Urinalysis Urine culture Blood culture CT MRI CVA tenderness Renal colic Flank pain − − + − − − − − − − − N Hematuria Ultrasound CT scan Colicky abdominal pain Dysuria Hollow Viscous Obstruction Small bowel obstruction Diffuse + − + − + − + − + + ± Hyperactive then absent Leukocytosis with left shift indicates complications Abdominal X ray Dilated loops of bowel with air fluid levels Gasless abdomen “Target sign”– , indicative of intussusception Venous cut-off sign” – suggests thrombosis Volvulus Diffuse – − + − + − − − Positive in perforated cases + + Hyperactive then absent Leukocytosis CT scan and abdominal X ray U shaped sigmoid colon “Whirl sign” Biliary colic RUQ − − + + − − − − − − − N ↑ bilirubin and alkaline phosphatase Ultrasound Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Vascular Disorders Ischemic causes Mesenteric ischemia Periumbilical Positive if bowel becomes gangrenous − + − − + + + Positive if bowel becomes gangrenous Positive if bowel becomes gangrenous − Hyperactive to absent Leukocytosis and lactic acidosis Amylase levels D-dimer CT angiography SMA or SMV thrombosis Also known as abdominal angina that worsens with eating Acute ischemic colitis Diffuse + ± + − − + + + + + + Hyperactive then absent Leukocytosis Abdominal x-ray Distension and pneumatosis CT scan Double halo appearance, thumbprinting Thickening of bowel May lead to shock Hemorrhagic causes Ruptured abdominal aortic aneurysm Diffuse ± − + − − − + + + − − N Fibrinogen D-dimer Focused Assessment with Sonography in Trauma (FAST)  Unstable hemodynamics Intra-abdominal or retroperitoneal hemorrhage Diffuse ± − ± − − − − + + − − N ↓ Hb ↓ Hct CT scan History of trauma Disease Abdominal Pain Fever Rigors and chills Nausea or vomiting Jaundice Constipation Diarrhea Weight loss GI bleeding Hypo- tension Guarding Rebound Tenderness Bowel sounds Lab Findings Imaging Comments Gynaecological Causes Tubal causes Torsion of the cyst/ovary RLQ / LLQ − − + − − − − − − ± ± N ↑ ESR ↑ CRP Ultrasound Sudden onset & severe pain Acute salpingitis RLQ / LLQ + ± − − − − − − − ± ± N Leukocytosis Pelvic ultrasound Vaginal discharge Cyst rupture RLQ / LLQ − − + − − − − − + ± ± N ↑ ESR ↑ CRP Ultrasound Pregnancy Ruptured ectopic pregnancy RLQ / LLQ − − + − − − − − + + + N Positive pregnancy test Ultrasound History of Missed period Vaginal bleeding Extra-abdominal causes Pulmonary disorders Pleural empyema RUQ/Epigastric + ± − − − − + − − − − N Thoracentesis Chest X-ray Pleural opacity Localization of effusion Physical examination Crackles Egophony Increased tactile fremitus Pulmonary embolism RUQ/LUQ ± − − − − − − − ± − − N ABGs D-dimer CXR V/Q scan Spiral CT pulmonary angiogram Dyspnea Tachycardia Pleuretic chest pain Pneumonia RUQ/LUQ + + + − − ± − − + − − Normal or hypoactive ABGs Leukocytosis Pancytopenia CXR CT chest Bronchoscopy Shortness of breath Cough Cardiovascular disorders Myocardial Infarction Epigastric ± − + − − − − − Positive in cardiogenic shock − − N Cardiac enzymes ECG Echocardiogram Wall motion abnormality Wall rupture Septal rupture Chest pain, tightness, diaphoresis Complications: Arrythmias Mitral regurgitation Ventricular wall rupture Septal rupture

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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]

This microchapter covers the incidence, prevalence, mortality, temporal trends, and demographic distribution (age, sex, race/ethnicity) of acute pancreatitis (AP) at global and national levels. Risk factors for developing AP are covered in a dedicated microchapter; etiology-specific epidemiology is referenced here only insofar as it explains demographic patterns.

Global incidence of AP is estimated at 13–49 per 100,000 person-years depending on region and methodology, with higher rates in high-income countries.^[1][2] In 2021, the Global Burden of Disease (GBD) study estimated 2.75 million incident cases of AP worldwide, with the highest burden in Eastern Europe (age-standardized pancreatitis incidence ~99 per 100,000, including acute and chronic forms).^[3][4] A landmark 2022 systematic review and meta-analysis (Iannuzzi et al., 44 studies) found the global incidence is increasing at 3.07% per year (95% CI 2.30%–3.84%), with increases observed in North America (AAPC 3.67%) and Europe (AAPC 2.77%).^[2]

In the United States, AP is among the most common GI causes of hospitalization, producing >288,000 admissions annually at a cost exceeding $2.6 billion.^[1][5] Hospitalization for AP increased approximately 30% over the past decade.^[1] A 2026 US population-based analysis (TriNetX, 120 million individuals) reported age-standardized incidence rising from 23 per 100,000 in 1999 to 117 per 100,000 in 2024 (AAPC 4.81%), though this higher figure likely reflects inclusion of outpatient encounters and coding changes in addition to true incidence increases.^[6] When restricted to inpatient admissions only, US incidence estimates are approximately 40–60 per 100,000.^[7]

The increase in AP incidence is likely multifactorial, potentially driven by rising rates of obesity, metabolic syndrome, and associated gallstone disease, as well as improved diagnostic recognition and coding.^[1][2] A 2026 US study found that alcohol-induced AP was the only etiology with a statistically significant increase in incidence since 2016, particularly among females.^[6]

Global trends from GBD 2021 show a nuanced picture: the overall global age-standardized incidence rate has slightly declined (APC −0.25%), but incidence is increasing in low and low-middle SDI countries.^[3] This divergence highlights growing disparities in AP burden by socioeconomic development.

Overall AP mortality (case fatality) is approximately 1%–2%, consistent with the pooled estimate of 1.97% (95% CI 1.55%–2.39%) from the Iannuzzi 2022 meta-analysis.^[1][2] Case fatality has decreased over time due to improvements in critical care and minimally invasive management, but the overall population mortality rate has remained relatively unchanged because of increasing incidence, with approximately 9,000 deaths in 2021 when all pancreatitis (acute and chronic) listed anywhere on the death certificate is considered, though only ~3,300 deaths in 2020 listed acute pancreatitis specifically as the underlying cause.^[5][8] In 2021, GBD estimated 122,420 AP deaths globally.^[3]

US pancreatitis mortality rates declined 18% from 2006–2019 but rose sharply (25%) from 2019–2021 during the COVID-19 pandemic. Mortality is highest among American Indian/Alaska Native persons and lowest among Asian/Pacific Islander individuals.^[5][9]

Deaths from alcohol-associated AP increased 120% from 2011–2020 while non-alcohol AP deaths remained stable. Among racial/ethnic groups, alcohol-associated AP mortality was highest in non-Hispanic Black individuals (0.21/100,000), whereas non-alcohol AP mortality was highest among AI/AN persons (1.13/100,000).^[8]

Severity-stratified mortality (persistent organ failure 25%–46%; infected necrosis with organ failure ~35%) is detailed in the Natural History, Complications, and Prognosis microchapter.

AP incidence increases with age. Peak burden occurs in middle-aged and older adults, with GBD data showing the highest rates among those ≥65 years. However, an upward incidence trend has been noted in younger adults aged 15–25.^[4]

Pediatric AP is now recognized as more common than previously appreciated. Incidence in children is estimated at 3.6–13.2 per 100,000 depending on methodology (inpatient-only vs. including outpatient encounters).^[10][11] A large US private insurance database estimated pediatric AP incidence at 12.3 per 100,000 when outpatient encounters were included.^[7] The global pediatric AP incidence is increasing at 5.44% per year (95% CI 0.52%–10.36%), faster than in adults.^[2] However, recent US data suggest the incidence may have stabilized since 2007–2014.^[7] Biliary/obstructive factors, medications, and systemic diseases are the most common causes of childhood AP, differing from the adult pattern. In the United Kingdom, childhood AP incidence was reported at 0.78 per 100,000/year, with a sevenfold higher rate among Pakistani children (4.55/100,000).^[12] Globally, GBD 2021 estimated a pediatric (ages 0–19) pancreatitis age-standardized incidence of 7.18 per 100,000, with declining mortality over time.^[13]

The risk of AP is similar between men and women overall.^[1] GBD 2021 data show a male-to-female incidence ratio of approximately 1.27:1 and a mortality ratio of 1.94:1.^[4] The higher mortality in men is largely attributable to higher rates of alcohol-related AP.

When stratified by etiology, important sex differences emerge:^[1]

• Gallstone AP is more common in women (reflecting higher gallstone prevalence)
• Alcohol-related AP is more common in men
• Hypertriglyceridemic AP, hypercalcemic AP, and malignancy-related AP are more common in men

The dose-response relationship between alcohol and AP also differs by sex: it follows a J-shaped (nonlinear) pattern in women but a monotonic increase in men.^[14]

AP disproportionately affects certain racial and ethnic minority groups:^[1]

• African Americans are approximately 2-fold more likely to develop AP compared with White Americans. They are also less likely to be transferred to tertiary care centers and more likely to live in underserved neighborhoods, implicating social determinants of health.^[1]
• Hispanic patients experience greater rates of organ failure (acute kidney injury and shock) and longer emergency department wait times.^[1]
• American Indian/Alaska Native persons have the highest pancreatitis mortality among all racial/ethnic groups in the US and experienced a sharp mortality increase during 2019–2021.
• New Zealand Māori have among the highest reported AP incidence rates worldwide, with a higher rate of gallstone pancreatitis compared with non-Māori.^[15]
• Asian individuals generally have the lowest AP prevalence and mortality.

Pancreatitis prevalence in the US is highest among Black and American Indian/Alaska Native individuals across multiple insurance databases.^[5]

AP generates substantial healthcare costs. In the US:

• >288,000 hospital admissions annually^[1]
• $2.6 billion in annual healthcare costs^[1]
• Gallstone AP has higher hospitalization charges than alcohol-related AP ($61,182 vs. $37,982) due to increased use of imaging, ERCP, and longer length of stay^[16]
• Disease severity is the key determinant of healthcare costs
• Pancreatitis claims-based prevalence was 0.19% among privately insured, 0.48% among Medicare, and 0.44% among Medicaid beneficiaries (2021)^[5]

1. Recognize that AP incidence is increasing, particularly alcohol-related AP in recent years, and maintain a broad differential for etiology.
2. Be aware of racial/ethnic disparities: African American and American Indian/Alaska Native patients face disproportionate AP burden and may benefit from targeted risk factor modification and equitable access to tertiary care.
3. Consider AP in children presenting with abdominal pain — pediatric AP is no longer rare (incidence overlaps with the lower end of adult ranges).
4. Recognize that AP mortality, while declining over decades, increased during the COVID-19 pandemic period, potentially reflecting delayed presentations and strained healthcare resources.

• AP is the most common GI cause of hospitalization in the US, with incidence rising ~3%–5% annually.
• Population-level case fatality is ~1%–2%, but this masks dramatic variation by severity (see Natural History microchapter for organ-failure and infected-necrosis rates).
• Gallstone AP predominates in women; alcohol-related AP predominates in men — but alcohol-related AP is now increasing in women.
• African Americans have 2× the AP risk, but American Indian/Alaska Native populations have the highest mortality.
• Pediatric AP is no longer rare — incidence of 3.6–13.2 per 100,000 overlaps with the lower adult range.
• Eastern Europe bears the highest global pancreatitis burden, driven largely by alcohol consumption.

• Assuming AP is rare in children — it is now recognized as one of the more common pediatric GI diagnoses requiring hospitalization.
• Overlooking racial/ethnic disparities and social determinants of health in AP outcomes.
• Attributing the entire incidence increase to a true rise in disease without considering coding and diagnostic detection changes.
• Failing to recognize that overall population mortality has not declined despite lower case fatality, because incidence has increased.

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]

The most common risk factors in the development of acute pancreatitis are gallstones (40%–70% of cases) and alcohol use (~20%–35% of cases). Other important risk factors include smoking, hypertriglyceridemia, obesity and metabolic syndrome, type 2 diabetes mellitus, certain medications, genetic variants, post-ERCP status, and pregnancy. Less common risk factors include hypercalcemia, autoimmune disease, infections, anatomic variants, pancreatic tumors, trauma, physical inactivity, ischemic/vascular insults, scorpion envenomation, cannabis use, idiopathic disease (a diagnostic category), celiac disease, inflammatory bowel disease, and chronic kidney disease.

Common risk factors in the development of acute pancreatitis include gallstones, alcohol, smoking, hypertriglyceridemia, obesity and metabolic syndrome, type 2 diabetes mellitus, selected medications, genetic predisposition, post-ERCP status, and pregnancy.

Gallstones are the most common cause of acute pancreatitis, accounting for 40%–70% of cases depending on the population studied.^[1] Migrating gallstones cause transient obstruction of the pancreatic duct.^[2][3] Risk factors for gallstone-related acute pancreatitis mirror those for gallstone disease itself: female sex, increasing age, obesity, rapid weight loss, pregnancy, and certain medications (e.g., estrogen, octreotide).^[3][4] In a large Chinese cohort (n=512,891), prevalent gallbladder disease carried an HR of 2.42 (95% CI 2.03–2.88) for acute pancreatitis.^[5] Biliary acute pancreatitis has the lowest recurrence rate among etiologies (approximately 12%), further reduced to approximately 7% after cholecystectomy.^[4]

Alcohol is the second most common cause of acute pancreatitis (~20%–35% of cases depending on the population studied).^[1][4] Prolonged heavy use (≥4–5 drinks/day for >5 years) is typically required; the overall lifetime risk among heavy drinkers is only 2%–5%, indicating that cofactors (genetic, smoking, metabolic) are necessary.^[3][4][6] Binge drinking without chronic heavy use has traditionally been considered insufficient to precipitate acute pancreatitis, though one Swedish cohort found that consuming ≥5 drinks on a single occasion increased risk by 52% after adjustment, suggesting the relationship may be more nuanced.^[3][6] The type of alcohol does not affect risk.^[3] The dose-response relationship differs by sex: monotonic increase in men but J-shaped (nonlinear) in women.^[6] Clinicians should be cautious about attributing acute pancreatitis to alcohol in moderate drinkers, as this produces stigmatization and delays identification of the true etiology.^[4] Alcohol potentiates pancreatic injury from other environmental and genetic risk factors.^[4][6]

Smoking is an independent risk factor for acute pancreatitis, separate from its strong association with alcohol use.^{[7][8][9][10][6]} A meta-analysis of 10 prospective studies found current smokers had RR 1.49 (95% CI 1.29–1.72) for acute pancreatitis versus never smokers, with a dose-response relationship (RR 1.30 per 10 cigarettes/day).^[10] A Korean population-based cohort (n=4.2 million) confirmed dose-dependent risk (HR 1.66 for ≥20 cigarettes/day) and showed that smoking cessation reduces risk (HR 1.34 for quitters versus 1.66 for continuous smokers).^[8] The combination of heavy drinking and smoking increases acute pancreatitis risk beyond either exposure alone, though estimates vary widely (RR 1.40–11.40) due to heterogeneous definitions of exposure.^[11] After two decades of cessation, risk returns to nonsmoker levels for non-gallstone acute pancreatitis.^[7] Mendelian randomization studies confirm that genetic predisposition to smoking independently elevates pancreatitis risk.^[6]

Hypertriglyceridemia accounts for 2%–7% of acute pancreatitis cases and is the third leading cause.^[4] Levels >1,000 mg/dL strongly predispose to acute pancreatitis, but recent data show even moderate elevations increase risk.^[4] Familial chylomicronemia syndrome carries up to a 76% lifetime risk of acute pancreatitis.^[4] HTG-associated acute pancreatitis is associated with the highest complication rates among all etiologies (highest rates of non-mild disease, ICU admission, and mortality).^[12][13] Triglycerides may be falsely low at presentation if the patient has been fasting.^[4] Recurrent episodes can be triggered by even modest elevations, emphasizing aggressive long-term triglyceride control.^[4] Recent RCT analyses show that lowering triglycerides by ≥40% (e.g., with apoC-III-targeting drugs) reduces acute pancreatitis risk.^[13] Secondary causes of hypertriglyceridemia (poorly controlled diabetes, alcohol, pregnancy, medications such as estrogen, tamoxifen, retinoids, protease inhibitors) should be identified and addressed.^[13]

Obesity (BMI ≥30) is an independent risk factor for both the occurrence and severity of acute pancreatitis.^[3][14] A 2025 meta-analysis (89 studies) found obesity significantly increased risk of severe acute pancreatitis (OR 3.06, 95% CI 1.37–6.83), local complications (OR 2.68), and systemic complications (OR 2.40).^[14] Waist circumference is positively associated with acute pancreatitis risk (HR 1.35 per 1-SD increase).^[5] Metabolic syndrome components (obesity, diabetes, hypertension, hypertriglyceridemia) have additive effects: individuals with ≥3 metabolic risk factors had an HR of 3.41 (95% CI 2.46–4.72) for acute pancreatitis compared with those with none.^[5]

Type 2 diabetes increases the risk of acute pancreatitis 2- to 3-fold.^[3] Diabetes also increases ICU admission odds (OR 1.65) and severe acute pancreatitis risk (OR 1.49).^[14] The relationship is bidirectional: acute pancreatitis itself leads to new-onset diabetes in approximately 23% of patients (covered in the Natural History microchapter).

Drug-induced acute pancreatitis accounts for a minority of cases.^[3][4] A systematic analysis of 1,060 cases found antineoplastics (16.9%), antibiotics (12.1%), and anticonvulsants (9.7%) were the most common drug classes.^[15] The drugs most strongly associated with acute pancreatitis are azathioprine, 6-mercaptopurine, didanosine (withdrawn from the US market), valproic acid, ACE inhibitors, and mesalamine.^[3][4] Drug-induced acute pancreatitis is generally mild, but severity varies by drug class—corticosteroids (40% mortality), antiprotozoals (31% mortality), and antiretrovirals (26% mortality) carry the highest severity and mortality (based on small case series of 19–30 patients per drug class; interpret with caution).^[15] Drug-induced acute pancreatitis occurs at a younger age than acute pancreatitis from other causes, and 21.6% of cases occur in children.^[15]

Regarding incretin-based therapies: Meta-analyses of cardiovascular outcomes trials show DPP-4 inhibitors are likely associated with a modest increase in pancreatitis risk (OR 1.63, 95% CI 1.12–2.37; moderate certainty), whereas GLP-1 receptor agonists show no increased risk (OR 0.96, 95% CI 0.68–1.35).^[16][17] A large 2025 Medicare/commercial claims study (>1.2 million patients per cohort) confirmed no increased acute pancreatitis risk with GLP-1 receptor agonists or DPP-4 inhibitors compared with SGLT2 inhibitors.^[18] However, both GLP-1 receptor agonists and DPP-4 inhibitors modestly increase biliary disease events, which could indirectly precipitate biliary acute pancreatitis.^[18] Caution is warranted in patients with a history of pancreatitis.^[17]

Mutations in PRSS1 (cationic trypsinogen), SPINK1, CFTR, CTRC (chymotrypsin C), CASR (calcium-sensing receptor), and CLDN2 (claudin-2) are associated with acute pancreatitis and chronic pancreatitis.^[3][19] These may act as cofactors—e.g., CLDN2 variants synergize with alcohol.^[3] Genetic factors account for approximately 50% of acute recurrent pancreatitis and approximately 75% of chronic pancreatitis in children.^[20][21] A recent pediatric study reported pathogenic variants in acute pancreatitis, acute recurrent pancreatitis, and chronic pancreatitis patients at varying rates; the expected pattern is increasing prevalence from first-episode acute pancreatitis to acute recurrent pancreatitis to chronic pancreatitis (exact percentages should be verified against the original source).^[21] A large multicenter INSPPIRE study (n=944 pediatric acute recurrent pancreatitis/chronic pancreatitis patients, 2026) using 14-gene next-generation sequencing found that 74% carried at least one genetic risk variant, with variants in PRSS1, CTRC, and SPINK1 significantly accelerating progression to chronic pancreatitis.^[22] Hereditary pancreatitis (PRSS1 mutations) is autosomal dominant with approximately 80% penetrance and carries substantially increased lifetime risk of pancreatic cancer.^[3]

Acute pancreatitis occurs after 5%–10% of ERCPs.^[2] Risk factors for post-ERCP pancreatitis include female sex, sphincter of Oddi dysfunction, difficult cannulation, pancreatic duct injection, and young age.^[23] Prevention strategies (rectal NSAIDs, pancreatic duct stenting) are covered in the treatment microchapter.

Acute pancreatitis during pregnancy is uncommon (0.2–2.2 per 1,000 pregnancies) but carries high maternal-fetal morbidity.^[24][25] Up to 60% of cases occur in the third trimester or early postpartum.^[24] Gallstones account for 65%–100% of pregnancy-associated acute pancreatitis, followed by hypertriglyceridemia (which physiologically increases 2- to 4-fold during pregnancy).^[24][26] Maternal mortality has decreased but remains concerning; fetal loss can reach 23% and adverse fetal outcomes up to 57%.^[24][25] Incidence increases in the first 2 years postpartum.^[26]

Less common risk factors in the development of acute pancreatitis include hypercalcemia, autoimmune pancreatitis, infections, anatomic variants, pancreatic or periampullary tumors, abdominal trauma, physical inactivity, ischemic/vascular causes, scorpion envenomation, cannabis use, idiopathic disease (diagnostic category), celiac disease, inflammatory bowel disease, and chronic kidney disease.

• Hypercalcemia: Any cause (hyperparathyroidism, malignancy) can precipitate acute pancreatitis.^[27]
• Autoimmune pancreatitis: Type 1 (IgG4-related) and type 2; distinct entity with specific treatment.^[27]
• Infections: Viral (mumps, CMV, hepatitis B, HIV), parasitic (Ascaris), and bacterial.^[27]
• Anatomic variants: Pancreas divisum and choledochocele—controversial as independent causes; may act as cofactors.^[3]
• Pancreatic/periampullary tumors: Should be considered in patients >40 years with unexplained acute pancreatitis.^[1]
• Abdominal trauma: Blunt or penetrating; also iatrogenic (post-surgical).^[27]
• Physical inactivity: Each 4 MET-h/day higher activity associated with HR 0.95 for acute pancreatitis.^[5]
• Ischemic/vascular causes: Perioperative hypotension, cardiopulmonary bypass surgery, and vasculitis (e.g., polyarteritis nodosa, SLE) are uncommon but recognized precipitants.^[27][4]
• Scorpion envenomation: Recognized cause in tropical/subtropical regions (e.g., Trinidad, Brazil, India); mechanism involves direct pancreatic toxicity.^[27]
• Cannabis use: Emerging data, including Mendelian randomization evidence, suggest cannabis (particularly synthetic cannabinoids) may be an underrecognized risk factor.^[6]
• Idiopathic: No identifiable cause is found in 15%–25% of cases after standard workup — this is a diagnostic category rather than a discrete risk factor. Further evaluation (EUS, MRCP, genetic testing) may be warranted.^[1][4]
• Celiac disease and inflammatory bowel disease: Associated with acute pancreatitis, likely through shared inflammatory or obstructive mechanisms.^[4]
• Chronic kidney disease: End-stage renal disease and advanced CKD are associated with increased acute pancreatitis risk and worse outcomes.^[4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Tarek Nafee, M.D. [2]

There is no established screening recommendations for pancreatitis in the general population.

There is no established screening recommendations for pancreatitis in the general population.

Template:WH Template:WS

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]

This section covers the clinical course of acute pancreatitis (AP) stratified by severity, the two-phase mortality model, local and systemic complications per the Revised Atlanta Classification, prognostic determinants, severity scoring systems, long-term sequelae (recurrence, progression to chronic pancreatitis, and new-onset diabetes), and vascular complications. Management of complications and severity classification definitions are covered in dedicated microchapters.

Approximately 80% of AP episodes are mild and self-limiting, resolving within 3–7 days with supportive care.^[1][2] Approximately 20% develop moderately severe or severe disease, with prolonged hospitalization and increased mortality.^[2]

• Mild AP: No organ failure or local complications. Symptoms typically improve within 48 hours; patients tolerate oral diet and are discharged within a week.^[1][3][2]
• Moderately severe AP: Transient organ failure (<48 hours) and/or local complications. Mortality is approximately 2%. Course may be prolonged over weeks due to local complications.^[3][2]
• Severe AP: Overall mortality of severe/necrotizing AP is approximately 15%–20%; mortality with persistent organ failure is 25%–46%, and is substantially higher with multiorgan failure.^[1][3][4][5]

Deaths in AP occur in two distinct phases:^[5][6]

1. Early phase (first 1–2 weeks): Deaths result from primary organ failure driven by SIRS and the systemic inflammatory cascade. This is “sterile” organ failure unrelated to infection. The window of opportunity for intervention is narrow, and treatment is largely supportive.^[5]
2. Late phase (after 2 weeks): Deaths result from infected pancreatic necrosis (IPN) and secondary septic organ failure. Among patients with necrotizing pancreatitis, approximately one-third develop infected necrosis, typically after the first 10–14 days. Late mortality is driven by sepsis and its consequences. However, a large Dutch cohort study (n=639) found that mortality among patients with organ failure alone was paradoxically higher than in those with organ failure plus infected necrosis (44% vs. 29%, p=0.04). This difference disappeared after excluding very early deaths within 10 days of admission (28% vs. 34%, p=0.33), suggesting that the paradox is driven by fulminant early sterile organ failure deaths occurring before infection has time to develop, rather than a protective effect of infected necrosis.^[7][3]

In a population-based study, the median interval from AP onset to death was 6 days, and from organ failure onset to death was 3 days.^[5] Notably, a large multicenter study found that early-onset persistent organ failure was not associated with higher mortality compared with late-onset persistent organ failure, and no association was found between duration of organ failure and mortality — suggesting that the timing of organ failure may be less prognostically important than its persistence.^[7] However, data on the prognostic impact of organ failure duration are conflicting. Schepers et al. (2019) found no association between duration of organ failure and mortality, whereas Singh et al. (2021) found that duration was significantly associated with mortality (p=0.006), and that sequential multiple organ failure carried the worst prognosis (mortality 69% vs. 30% for simultaneous and 12% for single organ failure).^[8]

• Persistent organ failure (>48 hours) is the prime determinant of mortality. Overall mortality in patients with persistent organ failure is approximately 40%.^[5]
• Transient organ failure (<48 hours) carries a mortality of 1.4%–10%.^[5]
• SIRS at admission is highly predictive of organ failure and severe disease.^[1]
• Infected necrosis substantially worsens prognosis — mortality of 15%–35% overall; however, infected necrosis with concomitant organ failure carries approximately 35% mortality whereas infected necrosis without organ failure carries only ~1.4% mortality. Approximately one-third of patients with necrotizing pancreatitis develop infected necrosis, typically 10–14 days after onset. Risk factors include >50% pancreatic necrosis (aOR 3.61), persistent organ failure (aOR 11.71), invasive mechanical ventilation (uOR 12.24, high certainty), gallstone etiology (aOR 2.35), and delayed enteral nutrition (aOR 2.09) (moderate-to-high certainty evidence).^{[9][1][10][11]}
• Obesity (BMI >30) is independently associated with increased severity and complications.^[1]

Local complications are classified by the Revised Atlanta Classification based on morphology and timing:^[1][4]

Timing	Fluid collections	Necrotic collections
<4 weeks	Acute peripancreatic fluid collection (APFC)	Acute necrotic collection (ANC)
≥4 weeks (encapsulated)	Pancreatic pseudocyst	Walled-off necrosis (WON)

Key points:

• APFCs are common and usually resolve spontaneously.^[4]
• Pseudocysts are encapsulated fluid collections without solid necrotic material, arising from ductal disruption.^[4]
• ANCs contain variable amounts of fluid and necrotic debris. Necrosis is purely peripancreatic in ~50% of cases.^[4]
• WON is a mature, encapsulated collection containing necrotic material; it is the target of intervention when infected.^[4][3]
• Infected necrosis should be suspected when clinical deterioration occurs (new fever, rising inflammatory markers) or when gas is visible within a necrotic collection on CT.^[1]
• Disconnected duct syndrome may occur as a long-term sequela of necrotizing pancreatitis when a segment of viable pancreas is isolated from the main duct by necrosis, predisposing to persistent collections or fistula.^[4][3]

Other local complications:

• Abdominal compartment syndrome: Sustained intra-abdominal pressure >20 mmHg with organ failure; consider in ventilated patients with severe AP.^[12]
• Gastric outlet/duodenal obstruction from inflammatory mass effect.^[12]
• Pancreatic duct disruption leading to pancreatic ascites or fistula.^[12]

• Splanchnic vein thrombosis (SVT): Reported incidence varies by population studied: approximately 4%–7% in unselected AP cohorts, 13% (95% CI 7%–23%) in a 2024 meta-analysis with systematic imaging, and 16%–22% in dedicated necrotizing pancreatitis cohorts. Most commonly involves the splenic vein, followed by portal and superior mesenteric veins. Usually asymptomatic; serious complications (variceal bleeding, ascites) are infrequent. The role of anticoagulation remains controversial. A 2022 meta-analysis (Anis et al.) found that anticoagulation improved recanalization rates (OR 0.51), but the largest prospective necrotizing pancreatitis cohort (Sissingh et al. 2024, n=432) found no difference in radiological or clinical outcomes with anticoagulation, with spontaneous recanalization in 62%. A 2025 global Delphi consensus favored anticoagulation for portal vein and SMV thrombosis but reached no consensus for isolated splenic vein thrombosis. Risks of bleeding into necrotic collections must be weighed, particularly in the acute setting. Long-term, patients may develop sinistral portal hypertension and gastric fundal varices.^{[3][13][14][15][16]}
• Pseudoaneurysm: Incidence 4%–6% in necrotizing pancreatitis; most commonly involves the splenic artery and gastroduodenal artery. Rupture causes life-threatening hemorrhage with mortality historically reported at 34%–52%, though more recent series report 14%–23%.^[17]

• Pulmonary: Pleural effusions (most common systemic complication), atelectasis, ARDS.^[12]
• Cardiovascular: Hypotension, hypovolemic shock, nonspecific ST-T changes mimicking MI, pericardial effusion.^[12]
• Renal: Acute kidney injury (prerenal from hypovolemia; intrarenal from systemic inflammation).^[12]
• Hematologic: DIC.^[12]
• Metabolic: Hypocalcemia (fat saponification), hyperglycemia.^[12]
• Other: Abdominal compartment syndrome, intestinal ileus/obstruction, GI bleeding.^[12]

• Overall AP mortality: ~1%–2% at the population level, though hospitalized cohort studies report rates up to 5%.^[3][1][18]
• Mild AP: Near-zero mortality.^[3]
• Moderately severe AP: ~2% mortality.^[3]
• Severe AP: Overall mortality of severe/necrotizing AP is approximately 15%–20%; mortality with persistent organ failure is 25%–46%, and is substantially higher with multiorgan failure.^[3][4][5]
• Sterile necrosis with organ failure: ~20% mortality; sterile necrosis without organ failure carries near-zero mortality.^[11]
• Infected necrosis: 15%–35% mortality overall; however, infected necrosis with concomitant organ failure carries approximately 35% mortality whereas infected necrosis without organ failure carries only ~1.4% mortality.^[1][10][11]

Post-discharge mortality is clinically significant: in a large multicenter cohort (n=2,613), first-year post-discharge mortality was 5.5%, with 3.0% dying in the first 90 days — nearly matching in-hospital mortality (3.5%). A Danish population-based study (n=28,759) confirmed a 5.0% 90-day post-discharge mortality (aHR 7.62 vs. matched controls), with risk remaining elevated for up to 5 years. Age, comorbidities, severity, and admission creatinine and glucose were independent risk factors for post-discharge death. This underscores the importance of structured post-discharge follow-up.^[19][20]

Per the ACG 2024 Guidelines, clinicians should assess multiple risk factors rather than relying on any single test or score:^[1]

Patient factors:

• Age >55 years
• Obesity (BMI >30)
• Altered mental status
• Comorbid disease (especially type 2 diabetes)

Clinical/laboratory markers:

• SIRS at admission (highly predictive of organ failure)^[1]
• Persistent SIRS >48 hours
• BUN >20 mg/dL or rising BUN (marker of hypovolemia)
• Hematocrit >44% or rising hematocrit
• Elevated/rising creatinine
• CRP (peaks at 48–72 hours; useful but delayed)^[1]

Radiographic markers:

• Pleural effusions or pulmonary infiltrates
• Multiple or extensive extrapancreatic collections

No single scoring system is established as a gold standard. All have limitations including cumbersomeness and high false-positive rates.^[3] Scoring tools should supplement, not replace, ongoing clinical assessment.^[3]

Score	Variables	Timing	Key Limitations
BISAP	5 variables (BUN >25, mental status, SIRS ≥2, age >60, pleural effusion)	First 24 hours	Limited validation in severe disease; does not include imaging
APACHE II	12 physiologic variables + age + chronic health	Admission and serial	Complex; designed for ICU patients; not routinely obtained in non-ICU setting
Ranson	11 criteria (5 at admission, 6 at 48 hours)	Requires 48 hours	Cannot be recalculated; delayed; cumbersome
Glasgow/Imrie	8 criteria	48 hours	Similar limitations to Ranson
Modified Marshall	Respiratory, renal, cardiovascular	Serial	Used to define organ failure per Atlanta; simple

BISAP scoring: Score ≥3 associated with substantially increased mortality (0: 0.1%, 1: 0.4%, 2: 1.6%, 3: 3.6%, 4: 7.4%, 5: 9.5%).^[21]

The ACG 2024 Guidelines emphasize that the presence of SIRS at admission and signs of hypovolemia (rising BUN, elevated hematocrit) are the most practical early predictors of severe disease.^[1]

The risk of recurrent AP after an index episode is approximately 17%–22% overall, with substantially higher rates in alcohol-associated (~29%), hypertriglyceridemia-associated (~30%), and idiopathic (~15%–25%) etiologies, and lower rates in biliary AP (~12%), which is further reduced to ~7% after cholecystectomy.^[22][23][3] Independent risk factors for recurrence include alcohol etiology, smoking, and history of necrosis.^[2] Persistent organ failure >48 hours during the index episode independently predicts recurrence (HR 3.52, 95% CI 1.22–10.19).^[24]

• 10% of patients with a first AP episode progress to chronic pancreatitis (CP).^[2][25]
• 36% of patients with recurrent AP develop CP.^[2][25]
• Risk factors: alcohol use (HR 8.79), smoking (HR 2.50), male sex, CTSI severity, and ≥3 recurrences.^[25][24]
• Nearly three-quarters of patients diagnosed with CP have a prior AP diagnosis.^[2]
• There is an increased lifetime risk of pancreatic cancer in those with AP (adjusted HR ~3.8 for pancreatic cancer mortality in post-pancreatitis diabetes), likely driven by chronic inflammation.^[2][26]

New-onset diabetes after AP is more common than previously recognized:

• 23% of patients develop diabetes following a first AP episode (meta-analysis of 24 studies).^[4][27]
• 15% develop diabetes within 12 months, with risk increasing >2-fold at 5 years.^[2][27]
• Earlier meta-analyses suggested that diabetes development was not strongly associated with AP severity; however, a larger 2023 meta-analysis found significantly higher odds of prediabetes/DM after severe and moderately severe AP (OR 4.32). Both immune/inflammatory mechanisms beyond simple beta-cell destruction and necrosis-related injury likely contribute.^[2][27][28]
• Preliminary longitudinal data show that among patients with normal baseline endocrine function after a single AP episode, 54% develop prediabetes or diabetes by year 4, with progression most dynamic in the first 2 years (preliminary data; awaiting full publication).^[29]
• Hyperglycemia during AP (peak glucose >200 mg/dL) is a strong predictor of early-onset diabetes (42.9% vs. 3.5%) (preliminary data; awaiting full publication).^[30]

Pooled prevalence of pancreatic exocrine insufficiency is 19% after mild AP and 33% after severe AP.^[4] Manifests as steatorrhea, malabsorption, and fat-soluble vitamin deficiency. Diagnosed by fecal elastase-1 or ¹³C-mixed triglyceride breath test.^[4]

1. Assess severity early and serially: Evaluate SIRS criteria, BUN, hematocrit, and mental status at admission and at 24–48 hours. Do not rely solely on scoring systems.^[1]
2. Recognize the two-phase model: Early mortality is driven by sterile organ failure (supportive care); late mortality by infected necrosis (source control).^[5]
3. Suspect infected necrosis when clinical deterioration occurs after initial improvement (typically >7–10 days), particularly new/persistent fever or rising inflammatory markers.^[1]
4. Monitor for vascular complications in necrotizing pancreatitis: consider CT angiography for unexplained hemorrhage (pseudoaneurysm).^[2]
5. Screen for diabetes in the 12 months to 5 years following AP, regardless of severity.^[2]
6. Assess for exocrine insufficiency in patients with persistent GI symptoms after AP, especially after severe/necrotizing disease.^[4]

1. Persistent organ failure >48 hours is the single most important prognostic factor — not the extent of necrosis per se.
2. SIRS at admission is the best early bedside predictor of severe disease.
3. Rising BUN within 24 hours is a simple, reliable marker of hypovolemia and poor prognosis.
4. Necrosis cannot be reliably assessed on CT before 72 hours — early CT for severity staging is not recommended.
5. Infected necrosis typically develops >7–10 days into the disease course; new fever or deterioration in a recovering patient should raise suspicion.
6. ~1 in 4 patients develops diabetes after AP, with higher risk after severe disease — plan post-discharge metabolic follow-up.
7. Pseudoaneurysm rupture is a rare but rapidly fatal complication — consider CT angiography for any unexplained drop in hemoglobin in a patient with necrotizing pancreatitis.

1. Over-relying on scoring systems (e.g., Ranson, APACHE II) instead of serial clinical assessment, SIRS monitoring, and trending BUN/hematocrit.
2. Obtaining early CT (within 48 hours) to assess severity — necrosis is not yet visible and the CT will likely be falsely reassuring.
3. Equating “no necrosis on CT” with mild disease — organ failure can occur without necrosis.
4. Neglecting long-term follow-up — failing to screen for diabetes, exocrine insufficiency, and chronic pancreatitis after discharge.
5. Anticoagulating isolated splenic vein thrombosis without individual risk-benefit assessment — no consensus exists; bleeding risk into necrotic collections must be weighed.
6. Using obsolete terminology (phlegmon, abscess, hemorrhagic pancreatitis) rather than current Revised Atlanta Classification terminology.