Acute Pancreatitis

Obstructive (mechanical) causes

• Gallstones: a stone impacted at the ampulla obstructs the pancreatic duct, raising intraductal pressure and driving premature zymogen activation. Most common cause overall; suggested by ALT >3x ULN, female sex, age >40, and rapid weight loss or bariatric surgery.
• Other obstruction: periampullary or pancreatic head adenocarcinoma (suspect in a painless-jaundice or older patient with no other cause), pancreas divisum, sphincter of Oddi dysfunction, ampullary stenosis, and Ascaris lumbricoides in endemic regions.

Toxic and metabolic causes

• Alcohol: second most common; sensitizes acinar cells to cholecystokinin, promotes protein plugging of small ducts, and generates toxic fatty-acid ethyl esters. Typically after years of heavy use, not a single binge.
• Hypertriglyceridemia: pancreatic lipase liberates free fatty acids that are directly cytotoxic and cause capillary sludging; classically occurs at levels above roughly 1,000 mg/dL. Look for poorly controlled diabetes, familial chylomicronemia, estrogen, or pregnancy in the stem.
• Hypercalcemia: from hyperparathyroidism or malignancy; calcium promotes intracellular trypsinogen activation.
• Drugs: azathioprine/6-mercaptopurine, valproate, didanosine, pentamidine, L-asparaginase, sulfonamides, thiazides, furosemide, and mesalamine. GLP-1 receptor agonists carry a labeled pancreatitis warning.

Traumatic, iatrogenic, and other

• Post-ERCP: the most common iatrogenic cause; rectal NSAID prophylaxis (indomethacin) is endorsed by ASGE for high-risk patients.
• Blunt abdominal trauma: handlebar injury compresses the pancreas against the vertebral column.
• Infection/ischemia/autoimmune: mumps, coxsackievirus, CMV, HIV; post-cardiac-surgery hypoperfusion or vasculitis; IgG4-related autoimmune pancreatitis with a sausage-shaped gland.
• Genetic: PRSS1 (hereditary, autosomal dominant), SPINK1, and CFTR mutations — think recurrent pancreatitis in a young patient.

Modifiable versus non-modifiable

• Modifiable: alcohol, tobacco (independent dose-related risk), obesity, hypertriglyceridemia, offending drugs, gallstone risk from rapid weight loss.
• Non-modifiable: age, genetic mutations, pancreas divisum, prior episode, and post-ERCP anatomy.

• Initial zymogens activation: Pancreatic acinar cells normally produce trypsinogen, amylase, lipase, and phospholipase A2 in inactive forms. In acute pancreatitis, a triggering event (obstruction, reflux, cellular injury) causes premature conversion of trypsinogen to trypsin by cathepsin B; trypsin then autocatalytically activates additional trypsinogen molecules and other zymogens, overwhelming the natural protease inhibitor systems (pancreatic secretory trypsin inhibitor)

• Inflammatory cascade amplification: Activated proteases damage the pancreatic acinar cell membrane and interstitium, releasing damage-associated molecular patterns (DAMPs) and triggering toll-like receptor signaling. This initiates local inflammatory response with recruitment of neutrophils and macrophages, producing TNF-α, IL-1, IL-6, and IL-8, which perpetuate inflammation even after zymogens are depleted

• Microvascular injury and pancreatic necrosis: Inflammatory mediators increase vascular permeability, causing interstitial edema (edematous pancreatitis) or frank pancreatic necrosis when perfusion drops below critical thresholds. The disrupted pancreatic architecture prevents normal enzyme secretion, trapping activated enzymes intrapancreatically. Pancreatic necrosis occurs in 20-30% of cases and is the strongest predictor of complications and mortality

• Systemic manifestation (SIRS) and multi-organ failure: Severe pancreatitis allows translocation of activated enzymes and inflammatory cytokines into the bloodstream via damaged pancreatic veins, causing systemic inflammatory response syndrome (SIRS) with potential acute respiratory distress syndrome (ARDS), acute kidney injury (prerenal azotemia from third-spacing), and shock

• Epigastric pain (cardinal feature): Sudden onset, severe epigastric pain that is constant and unremitting, typically radiating to the back (due to retroperitoneal inflammation). Pain is worse when supine and improves with sitting forward; distinguishes pancreatitis from other abdominal emergencies. In severe cases, pain may be incapacitating and unresponsive to opioids initially

• Associated gastrointestinal symptoms: Nausea and vomiting are present in 70-80% of cases; vomiting may be persistent and contributes to dehydration and electrolyte abnormalities. Some patients present with only vague epigastric discomfort if pancreatitis is mild, delaying diagnosis

• Physical examination findings: Epigastric tenderness without severe peritoneal signs (if peritonitis is present, consider perforation or infected necrosis); tachycardia and hypotension reflect third-spacing and intravascular volume depletion; fever is variable—low-grade fever may be present from inflammatory response alone, but high fever (>38.5°C) suggests infected pancreatic necrosis or abscess formation. Cullen sign (ecchymosis around umbilicus) and Grey Turner sign (flank ecchymosis) are rare but highly specific for hemorrhagic pancreatitis indicating massive retroperitoneal bleeding

• Laboratory abnormalities at presentation: Leukocytosis (WBC 10,000-15,000 common), hemoconcentration (elevated Hgb and Hct from dehydration), hyperglycemia (from acinar damage and catecholamine release), hypocalcemia (from saponification of fat and sequestration in retroperitoneum—severe hypocalcemia portends worse prognosis), hypoalbuminemia (third-spacing), elevated transaminases (especially ALT >3× AST suggests biliary etiology), elevated bilirubin in cholestasis pattern if biliary obstruction

• Important variant presentations: Fulminant pancreatitis with shock and multi-organ failure can occur within 24-48 hours; chronic pancreatitis may present with recurrent episodes of acute exacerbation; some patients present primarily with symptoms of underlying cause (e.g., jaundice from gallstone choledocholithiasis before pancreatitis develops)

• Serum pancreatic enzymes: Serum amylase and lipase are the primary diagnostic tests; elevation of either enzyme >3× upper limit of normal (ULN) in appropriate clinical context establishes diagnosis. Lipase is more specific and sensitive than amylase for acute pancreatitis and remains elevated longer (7-14 days vs 3-5 days); amylase is also produced by salivary glands and various cancers, reducing specificity. Lipase should not exceed 10× normal in uncomplicated pancreatitis—markedly elevated levels (>10× normal) suggest alternative diagnosis or severe disease with necrosis. Enzyme level does NOT correlate with disease severity—mild pancreatitis may have markedly elevated enzymes while severe necrotizing pancreatitis may have only moderately elevated levels

• Imaging studies: Contrast-enhanced CT (CECT) of abdomen and pelvis is the gold standard for assessing severity, identifying complications, and excluding alternative diagnoses. CECT findings: pancreatic enlargement and edema (edematous), pancreatic necrosis (non-enhancing areas after contrast), peripancreatic fluid collections, and presence/extent of necrosis. CT should be delayed 24-48 hours after symptom onset because early CT may underestimate necrosis (necrosis evolves over first week); however, perform urgent CT if diagnosis unclear or complications suspected. Transabdominal ultrasound is good initial test if available (identifies gallstones, biliary dilatation) but is operator-dependent and limited by bowel gas; useful for monitoring in uncomplicated cases. ERCP is diagnostic and therapeutic if choledocholithiasis is suspected (dilated CBD, elevated bilirubin, cholangitis signs)

• Revised Atlanta Classification diagnostic criteria (2012): Diagnosis requires 2 of 3 criteria: (1) characteristic abdominal pain (epigastric, constant, radiating to back), (2) serum lipase or amylase >3× ULN, (3) characteristic imaging findings on CECT or MRI. This replaces older Ranson and APACHE scoring systems for diagnosis though those systems remain useful for severity assessment

• Important diagnostic pitfalls: Macroamylasemia (amylase-immunoglobulin complexes) can cause false elevation of serum amylase; check urine amylase-to-creatinine clearance ratio (>1% suggests pancreatitis, <1% suggests macroamylasemia). Pancreatitis can occur with normal enzymes in fulminant disease or if present >1 week (enzymes have normalized); clinical judgment required. Elevated lipase can occur in renal failure, mesenteric ischemia, and other conditions—always correlate with clinical picture

• Fluid resuscitation (first-line, critical intervention): Aggressive IV crystalloid rehydration (normal saline or lactated Ringer's) is the cornerstone of treatment—pancreatitis causes massive third-spacing (40-50% of intravascular volume can be sequestered in retroperitoneum and ascites). **

Local complications (Revised Atlanta Classification terminology)

• Acute peripancreatic fluid collection: extravasated enzyme-rich fluid within the first 4 weeks, no wall, no necrosis; usually resolves spontaneously — do not drain.
• Pancreatic pseudocyst: a collection persisting beyond 4 weeks that develops a fibrous/granulation-tissue wall lacking an epithelial lining (hence pseudo). Signals: persistent pain, early satiety, palpable mass, or a re-rising amylase. Drain (endoscopic cystgastrostomy preferred) only if symptomatic, infected, or causing gastric outlet/biliary obstruction.
• Acute necrotic collection / walled-off necrosis: necrosis becomes encapsulated after ~4 weeks. Debridement should be delayed until the collection matures, using a step-up approach (percutaneous or endoscopic drainage first, then minimally invasive necrosectomy) rather than early open necrosectomy.
• Infected necrosis — emergency: bacterial translocation from the gut seeds necrotic tissue, typically after the first week. Signals: new fever, rising WBC, clinical deterioration, and retroperitoneal gas on CT. Requires a necrosis-penetrating antibiotic (carbapenem, e.g., meropenem) and drainage; prophylactic antibiotics in sterile necrosis are explicitly not recommended by ACG.

Vascular complications

• Splenic vein thrombosis: perivenous inflammation; produces isolated gastric varices with a normal liver — treated with splenectomy if bleeding.
• Pseudoaneurysm (splenic or gastroduodenal artery) — emergency: enzymatic erosion of an arterial wall; signals are sudden hematocrit drop, expanding mass, or GI bleed. Diagnose with CT angiography and treat with angioembolization.

Systemic complications

• SIRS, ARDS, and shock — emergency: circulating cytokines plus phospholipase A2 degradation of surfactant; hypoxemia within 48–72 hours.
• AKI, hypocalcemia from fat saponification, hyperglycemia, and later exocrine insufficiency or diabetes after extensive necrosis.

Treatment-related

• Over-resuscitation: excessive fluid worsens pulmonary edema and can precipitate abdominal compartment syndrome (a surgical emergency signaled by a tense abdomen, oliguria, and rising airway pressures).
• Parenteral nutrition: line sepsis and gut mucosal atrophy; enteral feeding is preferred.

• Lipase beats amylase: order lipase — it is more specific, rises earlier, and stays elevated 7–14 days. The classic distractor is using the magnitude of enzyme elevation to grade severity; it does not correlate with severity or prognosis.
• ALT is the gallstone clue: an ALT greater than three times normal in acute pancreatitis is the single best laboratory predictor of a biliary etiology. Next step is right upper quadrant ultrasound, not CT.
• The single most tested management step: for mild biliary pancreatitis, perform cholecystectomy during the index admission (ACG and AGA), not in 6 weeks — delayed surgery carries a high rate of recurrent pancreatitis or cholangitis.
• ERCP is not for everyone: urgent ERCP within about 24 hours is indicated only for concurrent acute cholangitis (or persistent biliary obstruction). Gallstone pancreatitis alone, without cholangitis, is not an ERCP indication — a frequent trap.
• No prophylactic antibiotics: ACG advises against antibiotics for sterile necrosis or for severity alone. Antibiotics are for infected necrosis (gas on CT, deterioration) or a documented extrapancreatic infection.
• Feed the gut early: early oral or enteral (nasogastric/nasojejunal) nutrition within the first 24–48 hours is preferred over NPO or TPN — it maintains mucosal integrity and reduces infectious complications.
• Fluids: lactated Ringer's, and not limitless: ACG favors lactated Ringer's over normal saline; large-volume saline promotes hyperchloremic acidosis. Aggressive over-resuscitation causes pulmonary edema and abdominal compartment syndrome, so titrate to clinical endpoints such as urine output, heart rate, and BUN trend.
• Buzzwords and associations: Cullen (periumbilical) and Grey Turner (flank) ecchymoses signal hemorrhagic disease; isolated gastric varices mean splenic vein thrombosis; recurrent pancreatitis in a young patient means *PRSS1*/*SPINK1*/*CFTR*; triglycerides above roughly 1,000 mg/dL are treated with insulin infusion and, in refractory cases, apheresis.