GET THE APP

Appropriate Search of the Etiologies of Acute Pancreatitis
Pancreatic Disorders & Therapy

Pancreatic Disorders & Therapy
Open Access

ISSN: 2165-7092

+44 1478 350008

Review Article - (2014) Volume 4, Issue 2

Appropriate Search of the Etiologies of Acute Pancreatitis

Pongprasobchai S*
Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Bangkok, Thailand
*Corresponding Author: Pongprasobchai S, Siriraj Hospital Medicine, Pran-Nok Road, Bangkok-Noi, Bangkok 10700, Thailand, Tel: 661-207-0903, Fax: 02-411-5013 Email:

Abstract

 Search of etiologies of acute pancreatitis (AP) is important but guidelines or recommendations are limited. In this review, the author summarized the common causes, how to diagnose them, how to address them as a cause of AP and proposes a practical 8-step approach to search the etiologies of AP

<

Keywords: Acute pancreatitis, Hypertriglyceridemia, Hypercalcemia, Vasculitis

Introduction

Acute pancreatitis (AP) is an important abdominal emergency which carries significant morbidity and mortality. There are varieties of etiologies that can account for AP (Table 1). Appropriate search of the etiologies of AP is essential due to the 2 reasons. First, some etiologies may need prompt intervention during the course of AP e.g. gallstone, hypertriglyceridemia, hypercalcemia and vasculitis, etc. Second, the identified causes can be eliminated to prevent further attack.

Etiologies Approximate frequency (%)
Common  
Alcohol 30-40
Gallstone 30-40
Idiopathic 10-20
Less common 10-20
Iatrogenic (post-ERCP, post-FNA, post-balloon-assisted enteroscopy)  
Hypertriglyceridemia  
Hypercalcemia  
Drugs  
Neoplasms  
Uncommon causes of pancreatic duct obstruction (choledocholcele, pancreas divisum, sphincter of Oddi dysfunction)  
Infections  
Vasculitis  
Ischemic  

ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasonography; FNA, fine needle aspiration

Table 1: Common etiologies of acute pancreatitis

Despite the importance, there are limited guidelines and recommendations regarding how to search the etiologies of AP appropriately [1-3]. In this review, the author will review, summarize the common causes, how to diagnose and address them as a cause of AP and propose a practical 8-step approach to search the etiologies of AP.

Common Etiologies

Common etiologies of AP and the frequencies are showed in Table 1

How to Diagnose each Etiology?

Alcohol

Alcohol is a well-known cause of chronic pancreatitis. However, it is not such straightforward in AP. Most studies on alcoholic AP showed that most patients had chronic use of alcohol (no single heavy binge can cause AP) but the doses of alcohol were usually increased more over a couple weeks before the attack [4,5]. However, there is no exact threshold dose of alcohol to initiate AP [6]. The attack of AP usually had 12-48 hours delay after the last binge (“the afternoon after the night before”) [4]. Thus, in patient with AP and history of drinking, it is sometimes difficult to judge whether this alcohol is enough to cause AP.

It is unclear whether other etiologies of AP should still be sought in patients who already had history of heavy drinking. In the author’s study of 78 patients with first episodes of AP, 58% of the patients drank alcohol for >80 g per day for >5 years. However, a thorough search demonstrated that 29% of these alcoholic patients had gallstones and hypertriglyceridemia, which could also be the causes of AP [7]. It may be difficult to tell which one was the real culprit. However, the author believes that if the other causes are found besides alcohol, they should also be counted and treated. Results of the author’s may support the strategy to exclude other common causes of AP before accusing the alcohol as a cause of AP.

Gallstone

The principle event that initiates gallstone pancreatitis is gallstone migration through the papilla [8]. Most of the gallstones (80%) have already passed and no longer been in the common bile duct. The most sensitive method to identify gallstone as a cause of AP is the combination of a 3-fold elevation of alanine transaminase (ALT) above upper normal limit and ultrasonography (US) of the gallbladder. Early meta-analysis reported that a 3-fold-elevated ALT had a sensitivity of 50% but a positive predictive value (PPV) of 95% for gallstone pancreatitis [9]. More recent studies showed the sensitivity and PPV of the 3-fold elevated ALT were 90% and 100%, respectively in one study [10] and 61% and 92%, respectively in another study [11]. Combination of ALT and US was shown to have the highest sensitivity of 98% and the highest PPV of 100% [10]. Therefore, every current guideline on AP recommends checking ALT and performing US in every AP patient within the first 1-2 days after admission [1,2,12-14].

Iatrogenic

AP can be caused by many gastrointestinal procedures i.e. endoscopic retrograde cholangiopancreatography (ERCP), endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of the pancreas and balloon-assisted enteroscopy. The incidence of post-ERCP pancreatitis is 2-9% [15] and post EUS-FNA pancreatitis is 0.4% [16]. In balloon-assisted enteroscopy, AP occurred in 0.2-0.5% after double-balloon enteroscopy (most performed via antergrade route) [17,18]. For single-balloon enteroscopy, there is only 1 case report [19]. The diagnosis of post-procedure pancreatitis is usually easy by the occurrence of AP within 24 hours after the procedures.

Hypertriglyceridemia

Hypertriglyceridemia, either primary or secondary, can cause AP. The most widely-accepted minimal level of triglyceride that can initiate AP is 1,000 mg/dL [20,21]. However, this number is rather arbitrary and not proven. Furthermore, many genetic mutations have now been shown to associate with the risk of pancreatitis e.g. protease serine 1 (PRSS1), serine protease inhibitor Kazal type 1 (SPINK1), cystic fibrosis transmembrane conductance regulator (CFTR), chymotrypsin C (CTRC) and calcium sensing receptor (CASR) mutations [22]. Recent study demonstrated that some hypertriglyceridemic pancreatitis patients actually have CFTR mutations [23]. The important point is that serum triglyceride level should be measured as soon as possible after admission in all cases of AP [24] because the level may fall rapidly after fasting [25].

Hypercalcemia

Hypercalcemia-induced pancreatitis usually occurred in the setting of undiagnosed hyperparathyroidism. No threshold level of serum calcium has been identified and there is study shown the presence of CFTR and SPINK1 mutation in one third of patients with AP from hyperparathyroidism [26]. Serum calcium should be measured in every patient with AP [24] as soon as possible after admission because the calcium level may fall after intravenous fluid replacement and in case of severe AP.

Drugs

Lists of drug-induced pancreatitis have been recently reviewed by Badalovet al. [27] and Nitsche et al. [28] It is the author’s belief that only drugs that have been classified as “definite” (has recurrence after re-challenge) should be counted as a cause of AP (Table 2). Furthermore, the other more common causes of AP, i.e. gallstone, hypertriglyceridemia and hypercalcemia should also be excluded before concluding the cause as drug-induced pancreatitis.

Acetaminophen
All-trans-retinoic acid
Amiodarone
L-asparaginase
Azathioprine
Azodisalicylate
Bezafibrate
Bortezomib
Cannabis
Capecitabine
Carbamazepine
Carbimazole
Clomiphene
Cimetidine
Cisplatin
Codeine
Cytarabine
Dapsone
Dexamethasone
Didanosine
Enalapril
Erythromycin
Estrogens
Hydrochlorothiazide
Furosemide
Ifosfamide
Interferon-a 2b
Isoniazid
Itraconazole
Lamivudine
Losartan
6-mercaptopurine
Meglumine
Mesalamine/olzalazine
Methimazole
Methyldopa
Metronidazole
Nelfinavir
Octreotide
Olanzepine
Omeprazole
Opiate
Oxyphenbutazone
Pentamidine
Phenformin
Pravastatin
Procainamide
Pyritonol
Simvastatin
Steroids
Stibogluconate
Sufamethoxazole/co-trimoxazole
Sulfasalazine
Sulindac
Tamoxifen
Tetracycline
Valproic acid

Table 2: Definite drug-induced AP (adapted from Bodalov et al. [27] and Nitsche et al. [28])

Neoplasms

The 3 most common types of neoplasm that cause AP are ampullary neoplasm (25% have AP) [29], intraductal papillary mucinous neoplasm (IPMN, particularly main duct type, 7% have AP) [30] and pancreatic ductal adenocarcinoma (5% have AP) [29], respectively. Pancreatic intraepithelial neoplasia (panIN) is a well-established precursor of pancreatic neoplasm but the lesion is usually small (<0.5 cm) [31] and there is no report to associate with AP. Therefore, it is recommended to perform computed tomography (CT) in every patient >40 years of age (if no other causes of AP has been identified) because one study has shown to identify neoplasms in a significant proportion after this age [32].

Unusual or controversial causes of pancreatic duct obstruction

There are some unusual or controversial causes of pancreatic duct obstruction that may cause AP. Some congenital anomalies (e.g. choledochocele, annular pancreas, etc) may associate with AP. Pancreas divisum is a controversial cause of AP and recurrent AP and has been critically reviewed [33,34]. Sphincter of Oddi dysfunction (SOD) is an even more controversial cause of AP and recurrent AP [35,36]. Since congenital anomalies are rare and pancreas divisum and SOD are controversial, the search of these conditions should be preserved for patients with recurrent AP, not after the first attack of AP.

Infections

There are varieties of infections that can cause AP and have been systemically reviewed by Parenti et al. [37]. In summary, they include viruses (HIV, cytomegalovirus, herpes simplex, hepatitis B, mumps, varicella-zoster, coxsackie B and echoviruses), bacteria (salmonella, leptospira, legionella, mycoplasma, rickettsia), fungi (aspergillus), parasites (ascaris) and protozoa (cryptosporidium, toxoplasma, malaria). The diagnoses are usually based on characteristic signs and symptoms of particular infections at the time of AP [37].

Vasculitides

AP due to vasculitides has been reported in systemic lupus erythematosus [38,39], polyarteritisnodosa [40], Wegener granulomatosis [41], Henoch-Schönleinpurpura [42] and Behcet disease [43]. Diagnosis is usually done by the presence of AP during the setting of these active diseases.

Ischemic

Ischemic AP is difficult to diagnose because it may be the result rather than the cause. However, it has been reported in patient post cardiac arrest [44]. In facing with AP patient who has shock or hypotension, other causes of AP should be ruled-out thoroughly before labeling it as ischemic AP.

How far should we go before labelling idiopathic AP?

Current guidelines suggest that the proportion of AP patients who would be labeled as idiopathic AP should be <10-20%. Thorough history taking, specific work-ups of the etiologies described above should be attempted and will elucidate the cause of AP in approximately 80-90% of the cases [7]. If no cause can be identified, EUS is recommended [45]. EUS may discover small gallstone, common bile duct stone, microlithiasis, small ampullary or pancreatic neoplasms and early chronic pancreatitis that could be presented as AP. Alternatively, MRCP can also be used although there is no comparison study to EUS. ERCP, due to the invasiveness, should be second to EUS [46] and preserved for recurrent AP or in case EUS or MRCP are unavailable.

The author had used this thorough approach in the author’s institution and could reduce the diagnosis of idiopathic AP down from 14% before to 5% after using the thorough search [7]. The etiologies that became increasing markedly after a systematic search were gallstone (from 22% to 37%) and miscellaneous causes (from 11% to 17%) [7].

Steps of searching the etiologies of AP

Currently, there are only few guidelines that specifically address how to search the etiologies of AP [1,2]. Based on these guideline [1,2] and more recent reviews[3,6,24,26]. The author proposes an 8-step search (Figure 1) as follows [7].

pancreatic-disorders-therapy-Eight-step-search-etiologies

Figure 1: Eight step search of etiologies of AP

1. Check liver biochemistry test and perform transabdominal US to rule out gallstone pancreatitis in all patients [1-3,12-14].

2. Check serum triglyceride in all patients at admission and before discharge [3,24].

3. Check serum calcium in all patients at admission and before discharge [3,24].

4. Review definite drugs that can cause AP.

5. Review other explainable causes of AP e.g. post-ERCP, post-FNA, post balloon-assisted enteroscopy, vasculitis, infections and trauma.

6. Review history, amount and duration of alcohol consumption. If the amount is >80 g per day for >5 years, then it may assume alcohol as the cause of AP.

7. If patient is >40 years of age, perform cross-sectional imaging to rule-out neoplasms [32].

8. Perform EUS to rule out small stones, small ampullary and pancreatic neoplasms and early chronic pancreatitis [45,47].

9. If no cause is identified, then the patient can be labeled as “idiopathic” AP.

References

  1. Toouli J, Brooke-Smith M, Bassi C, Carr-Locke D, Telford J, et al. (2002) Guidelines for the management of acute pancreatitis. J GastroenterolHepatol 17 Suppl: S15-39.
  2. Working Party of the British Society of Gastroenterology; Association of Surgeons of Great Britain and Ireland; Pancreatic Society of Great Britain and Ireland; Association of Upper GI Surgeons of Great Britain and Ireland (2005) UK guidelines for the management of acute pancreatitis. Gut 54 Suppl 3: iii1-9.
  3. Nordback I, Sand J, Andrén-Sandberg A (2007) Criteria for alcoholic pancreatitis. Results of an international workshop in Tampere, Finland, June 2006. Pancreatology 7: 100-104.
  4. Nordback I, Pelli H, Lappalainen-Lehto R, Sand J (2005) Is it long-term continuous drinking or the post-drinking withdrawal period that triggers the first acute alcoholic pancreatitis? Scand J Gastroenterol 40: 1235-1239.
  5. Nordback I, Pelli H, Lappalainen-Lehto R, Järvinen S, Räty S, et al. (2009) The recurrence of acute alcohol-associated pancreatitis can be reduced: a randomized controlled trial. Gastroenterology 136: 848-855.
  6. Sand J, Lankisch PG, Nordback I (2007) Alcohol consumption in patients with acute or chronic pancreatitis. Pancreatology 7: 147-156.
  7. Pongprasobchai S, Thamcharoen R, Manatsathit S (2009) Changing of the etiology of acute pancreatitis after using a systematic search. J Med Assoc Thai 92 Suppl 2: S38-42.
  8. Acosta JM, Ledesma CL (1974) Gallstone migration as a cause of acute pancreatitis. N Engl J Med 290: 484-487.
  9. Tenner S, Dubner H, Steinberg W (1994) Predicting gallstone pancreatitis with laboratory parameters: a meta-analysis. Am J Gastroenterol 89: 1863-1866.
  10. Ammori BJ, Boreham B, Lewis P, Roberts SA (2003) The biochemical detection of biliary etiology of acute pancreatitis on admission: a revisit in the modern era of biliary imaging. Pancreas 26: e32-35.
  11. Levy P, Boruchowicz A, Hastier P, Pariente A, Thevenot T, et al. (2005) Diagnostic criteria in predicting a biliary origin of acute pancreatitis in the era of endoscopic ultrasound: multicentre prospective evaluation of 213 patients. Pancreatology 5: 450-6.
  12. Forsmark CE, Baillie J; AGA Institute Clinical Practice and Economics Committee; AGA Institute Governing Board (2007) AGA Institute technical review on acute pancreatitis. Gastroenterology 132: 2022-2044.
  13. Pezzilli R, Uomo G, Zerbi A, Gabbrielli A, Frulloni L, et al. (2008) Diagnosis and treatment of acute pancreatitis: the position statement of the Italian Association for the study of the pancreas. Dig Liver Dis 40: 803-808.
  14. Tenner S, Baillie J, DeWitt J, Vege SS; American College of Gastroenterology (2013) American College of Gastroenterology guideline: management of acute pancreatitis. Am J Gastroenterol 108: 1400-1415.
  15. Freeman ML, Guda NM (2004) Prevention of post-ERCP pancreatitis: a comprehensive review. GastrointestEndosc 59: 845-864.
  16. Wang KX, Ben QW, Jin ZD, Du YQ, Zou DW, et al. (2011) Assessment of morbidity and mortality associated with EUS-guided FNA: a systematic review. GastrointestEndosc 73: 283-290.
  17. Pata C, Akyüz U, Erzin Y, Mutlu N, Mercan A, et al. (2010) Post-procedure elevated amylase and lipase levels after double-balloon enteroscopy: relations with the double-balloon technique. Dig Dis Sci 55: 1982-1988.
  18. Xin L, Liao Z, Jiang YP, Li ZS. (2011) Indications, detectability, positive findings, total enteroscopy, and complications of diagnostic double-balloon endoscopy: a systematic review of data over the first decade of use. GastrointestEndosc 74: 563-70.
  19. Sharma MK, Sharma P, Garg H, Sehgal L, Bhatia V (2011) Clinical acute pancreatitis following anterograde single balloon enteroscopy. Endoscopy 43 Suppl 2 UCTN: E20-21.
  20. Toskes PP (1990) Hyperlipidemic pancreatitis. GastroenterolClin North Am 19: 783-791.
  21. Fortson MR, Freedman SN, Webster PD 3rd (1995) Clinical assessment of hyperlipidemic pancreatitis. Am J Gastroenterol 90: 2134-2139.
  22. Chang YT, Chang MC, Su TC, Liang PC, Su YN, Kuo CH, et al. (2008) Association of cystic fibrosis transmembrane conductance regulator (CFTR) mutation/variant/haplotype and tumor necrosis factor (TNF) promoter polymorphism in hyperlipidemic pancreatitis. ClinChem 54: 131-8.
  23. Kemppainen E, Puolakkainen P (2007) Non-alcoholic etiologies of acute pancreatitis - exclusion of other etiologic factors besides alcohol and gallstones. Pancreatology 7: 142-146.
  24. Dominguez-Muñoz JE, Malfertheiner P, Ditschuneit HH, Blanco-Chavez J, Uhl W, et al. (1991) Hyperlipidemia in acute pancreatitis. Relationship with etiology, onset, and severity of the disease. Int J Pancreatol 10: 261-267.
  25. Felderbauer P, Karakas E, Fendrich V, Bulut K, Horn T, et al. (2008) Pancreatitis risk in primary hyperparathyroidism: relation to mutations in the SPINK1 trypsin inhibitor (N34S) and the cystic fibrosis gene. Am J Gastroenterol 103: 368-374.
  26. Badalov N, Baradarian R, Iswara K, Li J, Steinberg W, et al. (2007) Drug-induced acute pancreatitis: an evidence-based review. ClinGastroenterolHepatol 5: 648-661.
  27. Nitsche C, Maertin S, Scheiber J, Ritter CA, Lerch MM, et al. (2012) Drug-induced pancreatitis. CurrGastroenterol Rep 14: 131-138.
  28. Bakkevold KE, Arnesjo B, Kambestad B. (1992) Carcinoma of the pancreas and papilla of Vater: presenting symptoms, signs, and diagnosis related to stage and tumour site. A prospective multicentre trial in 472 patients. Norwegian Pancreatic Cancer Trial. Scand J Gastroenterol 27: 317-25.
  29. Jang JW, Kim MH, Jeong SU, Kim J, Park do H, Lee SS, et al. (2013) Clinical characteristics of intraductal papillary mucinous neoplasm manifesting as acute pancreatitis or acute recurrent pancreatitis. J GastroenterolHepatol 28: 731-8.
  30. Hruban RH, Takaori K, Klimstra DS, Adsay NV, Albores-Saavedra J, et al. (2004) An illustrated consensus on the classification of pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasms. Am J SurgPathol 28: 977-987.
  31. Choudari CP, Fogel EL, Sherman S, Lehman GA. (1998) Idiopathi pancreatitis: yield of ERCP correlated with patient age. Am J Gastroenterol 93: A1654.
  32. Pongprasobchai S, Rerknimitr R. (2012) Pancreas divisum and pancreatitis. Pancreat Disorders Ther 2:3.
  33. Fogel EL, Toth TG, Lehman GA, DiMagno MJ, DiMagno EP (2007) Does endoscopic therapy favorably affect the outcome of patients who have recurrent acute pancreatitis and pancreas divisum? Pancreas 34: 21-45.
  34. Steinberg WM. (2003) Controversies in clinical pancreatology: should the sphincter of Oddi be measured in patients with idiopathic recurrent acute pancreatitis, and should sphincterotomy be performed if the pressure is high? Pancreas 27: 118-21.
  35. Steinberg WM, Chari ST, Forsmark CE, Sherman S, Reber HA, et al. (2003) Controversies in clinical pancreatology: management of acute idiopathic recurrent pancreatitis. Pancreas 27: 103-117.
  36. Parenti DM, Steinberg W, Kang P (1996) Infectious causes of acute pancreatitis. Pancreas 13: 356-371.
  37. Makol A, Petri M (2010) Pancreatitis in systemic lupus erythematosus: frequency and associated factors - a review of the Hopkins Lupus Cohort. J Rheumatol 37: 341-345.
  38. Derk CT, DeHoratius RJ (2004) Systemic lupus erythematosus and acute pancreatitis: a case series. ClinRheumatol 23: 147-151.
  39. Laharie D, Neau D, Halle O, Longy-Boursier M, Durandeau A, et al. (1997) [Uncommon etiology of acute pancreatitis: periarteritisnodosa]. GastroenterolClinBiol 21: 630-632.
  40. Chawla S, Atten MJ, Attar BM (2011) Acute pancreatitis as a rare initial manifestation of Wegener's granulomatosis. A case based review of literature. JOP 12: 167-169.
  41. Frigui M, Lehiani D, Koubaa M, Bouaziz Z, Abid B, et al. (2011) Acute pancreatitis as initial manifestation of adult Henoch-Schonleinpurpura: report of a case and review of literature. Eur J GastroenterolHepatol 23:189-92.
  42. Le Thi Huong D, Wechsler B, Dell'Isola B, Lautier-Frau M, Palazzo L, et al. (1992) Acute pancreatitis in Behçet's disease. Dig Dis Sci 37: 1452-1453.
  43. Piton G, Barbot O, Manzon C, Moronval F, Patry C, et al. (2010) Acute ischemic pancreatitis following cardiac arrest: a case report. JOP 11: 456-459.
  44. Wilcox CM, Varadarajulu S, Eloubeidi M (2006) Role of endoscopic evaluation in idiopathic pancreatitis: a systematic review. GastrointestEndosc 63: 1037-1045.
  45. Pérez-Mateo M (2006) How we predict the etiology of acute pancreatitis. JOP 7: 257-261.
  46. Yusoff IF, Raymond G, Sahai AV (2004) A prospective comparison of the yield of EUS in primary vs. recurrent idiopathic acute pancreatitis. GastrointestEndosc 60: 673-678.
Citation: Pongprasobchai S (2014) Appropriate Search of the Etiologies of Acute Pancreatitis. Pancreat Disord Ther 4:135.

Copyright: © 2014 Pongprasobchai S, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top