Table 3

Non-drug causes of AP that were excluded in the 44 studies that included exclusion of non-drug causes as part of the DIP diagnostic process

Study	Biliary (n=35)	Alcohol (n=31)	Anatomic anomalies (n=21)	Hyper-triglyceridaemia (n=14)	Hyper-calcaemia (n=15)	Infection (n=16)	Recent trauma or surgery (n=13)	Genetic causes (mainly paediatric cases) (n=12)	Autoimmune disease (n=8)
Mallory and Kern68	Yes	Yes
Wyllie et al 14	Yes	Yes	Yes	Hyper-cholesterolaemia	Yes	Yes	History	Cystic fibrosis, hereditary pancreatitis
Steinberg24	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Hereditary pancreatitis
McArthur29	US — asymptomatic cholelithiasis and DIP may coexist in older patients					Hepatitis, EBV, CMV, etc
Fernandez et al 30	Yes	Yes
Chetaille et al 32	Yes	Yes	Yes			Yes	Yes
Eland et al 34	Yes	Yes
Delcenserie36	History, risk factors (female,>45 years, multiparous, obese, hypertriglyceridaemia), US, labs. See comments below*	History, clinical exam, Labs (mean globulin volume, ALT, AST). DIP may occur concurrently with alcohol-induced AP.	Difficult to diagnose in the acute phase due to inflammation, but after resolution of AP, may be identified on US, etc.: ductal AP (pancreas divisum and canalic stenoses…often neoplastic)			Suspect if concurrent sepsis or diarrhoeal syndrome—see list of agents below†		Younger patients: mutation of cationic trypsinogen. A sweat test is conclusive, especially in the presence of respiratory, sinus, or sterility problems. A mutation assessment of the CFTR gene may confirm cystic fibrosis	If concurrent cutaneous, joint, or other autoimmune manifestations: lupus, mixed connective tissue disorders, or periarteritis nodosa). May be confirmed through evaluation for an inflammatory distal-thrombotic syndrome or specific autoantibodies
Chaudhari et al 38	Imaging	Yes
Trivedi and Pitchumoni67	Yes	Yes	Yes	Yes	Yes	See list below‡	Yes	Cationic trypsinogen gene mutation, CFTR mutation, SPINK-1 mutation	Vasculitis, systemic lupus erythematosus, polyarteritis nodosum
Werlin and Fish39	Labs, imaging		Imaging			Lab	Clinically	Lab
Dhir et al 20	US	Yes	If AP continues after drug withdrawal or withdrawal/ substitution not possible: MR pancreaticography, ERCP, endoscopic U/S, CT, sphincter of Oddi manometry. Exclude tumour if patient >50 years and weight loss, painless jaundice, or new onset diabetes	Labs				Consider ruling out if AP continues after drug withdrawal or withdrawal/substitution not possible
Kemppainen and Puolakkainen40	Yes. If recurrent AP conduct MRCP/ERCP/manometry	Yes	Yes. If recurrent AP, conduct MRCP/ERCP/manometry	Labs	Labs	History	History, US, EUS, CT, MRI	History of cystic fibrosis; conduct genetic testing in some cases	History
Mennecier et al 41	US, CT, EUS	History, serum carboxy deficient transferrin (CDT) >2.6%, with no evidence favouring a biliary cause or other	Yes	Labs	Labs	If no obvious cause—see list of agents to exclude below§	History	If no obvious cause, exclude mutations of cationic trypsinogen and CFTR gene	If no obvious cause, test rheumatoid factor, ANA
Nguyen-Tang et al 42	Labs, EUS, cholangio-MRI	Yes	Yes			In younger patients: Coxsackie virus, mumps, CMV, Salmonella, Campylobacter, Mycoplasma, Legionella		Yes	Yes
Weersma et al 43	US	Yes
Anonymous21	History, labs, US and contrast-enhanced CT	History, previous admission	US and contrast-enhanced CT	Labs	Labs		History
Nitsche et al 48	Yes	Yes	Duct obstruction, aside from gallstones, and tumour	Yes	Yes	If no obvious other cause			Yes
Spanier et al 52	Liver function tests; EUS, ERCP, or MRCP	History	Various imaging techniques mentioned but use to eliminate specific etiologies not discussed (US, CT, MRCP, ERCP, EUS)	Yes	Yes			Mutations in cationic trypsinogen, SPINK-1, and CFTR genes
Ledder et al 56			Some may be associated with the underlying disease			Yes, but difficult to entirely exclude in most cases
Sunga et al 61	Abdominal imaging	Yes		Yes
Cofini et al 63			CT, ERCP, and EUS to exclude biliary and pancreatic duct abnormalities					Cystic fibrosis, chronic pancreatitis
Jones et al 64	History, liver function tests, US (abdominal and endoscopic)	History	Abdominal and endoscopic US	Labs	Labs		History
Studies that reported ‘ exclusion of all other causes ’, without explicitly defining all other causes
Haber et al 25	Yes	Yes
Scarpelli26
Delcenserie et al 27	US, labs, ERCP (risk may be too high if not suggestive of biliary AP), endoscopic cholangi-wirsungography (±bile collection for crystal/sludge evaluation), EUS	History, exam, labs (mean globulin volume, GGT, AST)	Endoscopic cholangi-wirsungography, biliary manometry, EUS		Yes	See list below¶	History
Maxson et al 16						Concurrent opportunistic infections were evaluated
Chambon et al 17	Imaging		Imaging
Lankisch et al 28	US	History
Maringhini et al 31
Berthelemy and Pariente33	Yes	Yes	Yes
Balani and Grendell6	History, labs, US, contrast-enhanced CT?	History	Contrast-enhanced CT	Labs	Labs		History
Ando et al 44	Yes	Yes							Yes
Ahmad and Mahmud46	Bilirubin and US				Labs	Hepatitis, EBV, CMV, etc
Butt et al 47	Yes	Yes
Vinklerová et al 49
Barreto et al 51	US	History, previous admission	MRCP to rule out congenital malformations, CT (if initial lab workup inconclusive) and serum CA 19–9 levels if suspected malignancy	Labs	Labs	Yes, if patient developed a severe viral illness necessitating admission	History		MR cholangiopancreatography, and markers, including immunoglobulin 4 (IgG4) and autoantibodies, as well as an endoscopic ultrasonography and fine needle aspiration
Marot et al 53
Meftah et al 54	Yes	Yes
Yanar et al 58
Heap et al 59
Ruellan et al 60	History of cholecystectomy, bile sampling	Yes			Yes
Tenner62	Yes	History	Yes, occur in 10%–15% of the population but controversial as to whether they cause AP (combination of anatomical and genetic factors may predispose)	Yes	Labs			Unclear
Nesvaderani et al 65	CT/imaging	History					History

*Absence of stones or hepatic damage on blood work does not formally exclude biliary cause. Consider EUS and/or bile evaluation for crystals/sludge. Biliary AP can occur concurrently with DIP—some medications can cause formation of drug crystals (ceftriaxone) or cholesterol crystals (clofibrate, octreotide) and result in AP due to gallstone migration. As well, morphine derivatives may cause sphincter of Oddi spasm in cholecystectomised patients, leading to biliary pain, cytolysis and AP.
†Infections to exclude: Coxsackie virus, mumps, HAV, HBV, HCV, CMV, Mycobacteria, Legionella, Chlamydia, Mycoplasma, Salmonella, brucellosis, Yersinia, Campylobacter, roundworms, hydatid cysts, tapeworms, fungal infections.
‡Infections to exclude: ascariasis, clonorchiasis, mumps, Rubella, HAV, HBV, HCV, Coxsackie B, Echo, adenovirus, CMV, EBV, HIV), Mycoplasma, C. jejuni, Leptospirosis, Legionella, Mycobacterium tuberculosis, Mycobacterium avium complex.
§Infections to exclude: hepatitis, Coxsackie virus B1-B6, echovirus, mononucleosis, EBV, measles, herpes zoster, CMV, Yersinia, Brucella, Legionella, Mycoplasma pneumoniae, Salmonella, Chlamydiae trachomatis and pneumoniae.
¶Recommended infections to exclude: Coxsackie virus, mumps, hepatitis viruses, CMV, Mycobacteria, Legionella, Chlamydia, Mycoplasma, Salmonella, brucellosis, Yersinia, Campylobacter, roundworm, hydatid cyst, tapeworm, fungal.
AP, acute pancreatitis; AST, aspartate aminotransferase; CFTR, cystic fibrosis transmembrane conductance regulator; CMV, cytomegalovirus; CT, computed tomography; DIP, drug induced pancreatitis; EBV, Epstein Barr virus; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; GGT, gamma-glutamyl transferase; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; MR, magnetic resonance; MRCP, magnetic resonance cholangiopancreatography; MRI, magnetic resonance imaging; SPINK1, serine peptidase inhibitor Kazal type 1; US, ultrasound.