Acute pancreatitis risk factors

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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]

Overview

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

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 (Biliary Disease)

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

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

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 (HTG)

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 and Metabolic Syndrome

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 Mellitus

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).

Medications (Drug-Induced Acute Pancreatitis)

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]

Genetic/Hereditary Factors

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]

ERCP (Post-Procedural)

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.

Pregnancy

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

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]

References

  1. ↑ 1.0 1.1 1.2 1.3 Tenner S, Vege SS, Sheth SG; et al. (2024). "American College of Gastroenterology Guidelines: Management of Acute Pancreatitis". Am J Gastroenterol. 119 (3): 419–437. doi:10.14309/ajg.0000000000002645.
  2. ↑ 2.0 2.1 Mederos MA, Reber HA, Girgis MD (2021). "Acute Pancreatitis: A Review". JAMA. 325 (4): 382–390. doi:10.1001/jama.2020.20317. PMID 33496779 Check |pmid= value (help).
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 Forsmark CE, Vege SS, Wilcox CM (2016). "Acute Pancreatitis". N Engl J Med. 375 (20): 1972–1981. doi:10.1056/NEJMra1505202. PMID 27959604.
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 4.16 Trikudanathan G, Yazici C, Evans Phillips A, Forsmark CE (2024). "Diagnosis and Management of Acute Pancreatitis". Gastroenterology. 167 (4): 673–688. doi:10.1053/j.gastro.2024.02.052.
  5. ↑ 5.0 5.1 5.2 5.3 Pang Y, Kartsonaki C, Turnbull I; et al. (2018). "Metabolic and Lifestyle Risk Factors for Acute Pancreatitis in Chinese Adults: A Prospective Cohort Study of 0.5 Million People". PLoS Med. 15 (8): e1002618. doi:10.1371/journal.pmed.1002618. PMID 30086132.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 Wang F, Görgülü K, Algül H, Hu LH (2026). "The Role of Alcohol in Pancreatic Diseases: A Comprehensive Perspective". Gastroenterology. 170 (2): 268–286. doi:10.1053/j.gastro.2025.08.025.
  7. ↑ 7.0 7.1 Sadr-Azodi O, Andrén-Sandberg Å, Orsini N, Wolk A (2012). "Cigarette Smoking, Smoking Cessation and Acute Pancreatitis: A Prospective Population-Based Study". Gut. 61 (2): 262–7. doi:10.1136/gutjnl-2011-300566. PMID 21836026.
  8. ↑ 8.0 8.1 Lee JM, Han KD, Lee SH; et al. (2023). "The Association Between Smoking, Changes in Smoking Behavior, and Acute Pancreatitis: A Population-Based Cohort Study in Korea". J Gastroenterol Hepatol. 38 (3): 451–459. doi:10.1111/jgh.16061.
  9. ↑ Ye X, Lu G, Huai J, Ding J (2015). "Impact of Smoking on the Risk of Pancreatitis: A Systematic Review and Meta-Analysis". PLoS One. 10 (4): e0124075. doi:10.1371/journal.pone.0124075. PMID 25879541.
  10. ↑ 10.0 10.1 Aune D, Mahamat-Saleh Y, Norat T, Riboli E (2019). "Tobacco Smoking and the Risk of Pancreatitis: A Systematic Review and Meta-Analysis of Prospective Studies". Pancreatology. 19 (8): 1009–1022. doi:10.1016/j.pan.2019.09.004.
  11. ↑ Adeniran EA, Jiang Y, Yadav D; et al. (2025). "Multiple Substance Use and the Risk of Pancreatitis: A Systematic Review". Therap Adv Gastroenterol. 18. PMID 40873658 Check |pmid= value (help).
  12. ↑ Bálint ER, Fűr G, Kiss L; et al. (2020). "Assessment of the Course of Acute Pancreatitis in the Light of Aetiology: A Systematic Review and Meta-Analysis". Sci Rep. 10 (1): 17936. doi:10.1038/s41598-020-74943-8. PMID 33087771 Check |pmid= value (help).
  13. ↑ 13.0 13.1 13.2 Subramanian S, Soran H, Sikora Kessler A; et al. (2025). "Prevention and Treatment of Hypertriglyceridemia-Mediated Acute Pancreatitis: A Narrative Review". Eur J Intern Med. doi:10.1016/j.ejim.2025.106648.
  14. ↑ 14.0 14.1 14.2 Dobszai D, Obeidat M, Szalai EÁ; et al. (2025). "Metabolic Syndrome Components Individually Worsen the Outcome of Acute Pancreatitis: A Systematic Review and Meta-Analysis". Front Endocrinol. 16: 1690754. doi:10.3389/fendo.2025.1690754.
  15. ↑ 15.0 15.1 15.2 Meczker Á, Hanák L, Párniczky A; et al. (2020). "Analysis of 1060 Cases of Drug-Induced Acute Pancreatitis". Gastroenterology. 159 (5): 1958–1961.e8. doi:10.1053/j.gastro.2020.07.016.
  16. ↑ Kanie T, Mizuno A, Takaoka Y; et al. (2021). "Dipeptidyl Peptidase-4 Inhibitors, Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Co-Transporter-2 Inhibitors for People With Cardiovascular Disease: A Network Meta-Analysis". Cochrane Database Syst Rev (10): CD013650. doi:10.1002/14651858.CD013650.pub2.
  17. ↑ 17.0 17.1 Pratley R, Saeed ZI, Casu A (2024). "Incretin Mimetics and Acute Pancreatitis: Enemy or Innocent Bystander?". Curr Opin Gastroenterol. 40 (5): 404–412. doi:10.1097/MOG.0000000000001057.
  18. ↑ 18.0 18.1 Fang YE, Paik JM, Ortega-Montiel J; et al. (2025). "Risk of Acute Pancreatitis and Biliary Events After Initiation of Incretin-Based Medications in Patients With Type 2 Diabetes". Diabetes Care. 48 (12): 2127–2137. doi:10.2337/dc25-1840.
  19. ↑ Mayerle J, Sendler M, Hegyi E; et al. (2019). "Genetics, Cell Biology, and Pathophysiology of Pancreatitis". Gastroenterology. 156 (7): 1951–1968.e1. doi:10.1053/j.gastro.2018.11.081.
  20. ↑ Uc A, Husain SZ (2019). "Pancreatitis in Children". Gastroenterology. 156 (7): 1969–1978. doi:10.1053/j.gastro.2018.12.043.
  21. ↑ 21.0 21.1 Ahmed F, Abu-El-Haija M (2025). "Acute Pancreatitis in Children: It's Not Just a Simple Attack". Gastroenterology. 169 (4): 572–584. doi:10.1053/j.gastro.2025.04.001.
  22. ↑ Abu-El-Haija M, Zhang W, Wang F; et al. (2026). "Pancreatitis Risk Genes Play a Major Role in Pediatric Pancreatitis: Insights From the INSPPIRE Study". Clin Gastroenterol Hepatol. PMID 42303027 Check |pmid= value (help).
  23. ↑ Dumonceau JM, Kapral C, Aber L; et al. (2020). "ESGE Guideline: Prophylaxis of Post-ERCP Pancreatitis". Endoscopy. 52 (3): 248–263. doi:10.1055/a-1091-7639. PMID 32126565 Check |pmid= value (help).
  24. ↑ 24.0 24.1 24.2 24.3 Lightner AL, Mathis KL (2022). "Surgery in Pregnancy". Am J Gastroenterol. 117 (10S): 53–59. doi:10.14309/ajg.0000000000001961.
  25. ↑ 25.0 25.1 Kumar-M P, Singh AK, Samanta J; et al. (2022). "Acute Pancreatitis in Pregnancy and Its Impact on the Maternal and Foetal Outcomes: A Systematic Review". Pancreatology. 22 (2): 210–218. doi:10.1016/j.pan.2021.12.007.
  26. ↑ 26.0 26.1 Maringhini A, Rossi M, Patti R, Maringhini M, Vassallo V (2024). "Acute Pancreatitis During and After Pregnancy: A Review". J Clin Med. 13 (7): 2028. doi:10.3390/jcm13072028.
  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 Boxhoorn L, Voermans RP, Bouwense SA; et al. (2020). "Acute Pancreatitis". Lancet. 396 (10252): 726–734. doi:10.1016/S0140-6736(20)31310-6. PMID 32891214 Check |pmid= value (help).
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