Significant Elevations of Serum Lipase Not Caused by Pancreatitis: a Systematic Review

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REVIEW ARTICLE Significant elevations of serum lipase not caused by pancreatitis: a systematic review

Ahmer M. Hameed1, Vincent W. T. Lam1,2 & Henry C. Pleass1,2

1Department of Surgery, Westmead Hospital, Westmead, NSW, Australia and 2Discipline of Surgery, University of Sydney, Sydney, NSW, Australia Abstract Background: Many authors advocate lipase as the preferred serological test for the diagnosis of pancreatitis and a cut-off level of three or more times the upper limit of normal (ULN) is often quoted. The literature contains no systematic review that explores alternative causes of a lipase level over three times as high as the ULN. Such a review was therefore the objective of this study. Methods: The EMBASE and MEDLINE databases (1985 to August 2013) were searched for all eligible articles. Predetermined data were extracted and independently analysed by two reviewers. Results: In total, data from 58 studies were included in the final analysis. The following causes other than pancreatitis of lipase levels exceeding three times the ULN were found: reduced clearance of lipase caused by renal impairment or macrolipase formation; other hepatobiliary, gastroduodenal, intestinal and neoplastic causes; critical illness, including neurosurgical pathology; alternative pancreatic diagnoses, such as non-pathological pancreatic hyperenzymaemia, and miscellaneous causes such as diabetes, drugs and infections. Conclusions: A series of differential diagnoses for significant serum lipase elevations (i.e. exceeding three times the ULN) has been provided by this study. Clinicians should utilize this knowledge in the interpretation and management of patients who have lipase levels over three times as high as the ULN, remaining vigilant for an alternative diagnosis to pancreatitis. The medical officer should be aware of the possibility of incorrect diagnosis in the asymptomatic patient.

Received 2 March 2014; accepted 17 April 2014

Correspondence Ahmer M. Hameed, Westmead Hospital, Cnr Darcy Road and Hawkesbury Road, Westmead, NSW 2145, Australia. Tel: + 61 2 9845 5555. Fax: + 61 2 989 374 40. E-mail: [email protected], aham2438 @uni.sydney.edu.au

Introduction sensitivity in the diagnosis of acute pancreatitis caused by alcohol consumption, and also in patients presenting later in their clinical Pancreatitis is an inflammatory disorder of the pancreas, the clini- course.6 cal course of which ranges from mild disease to multiple organ Lipase is an enzyme that catalyses the breakdown of dysfunction and death. Guidelines for the diagnosis of pancreatitis triglycerides.7 In addition to pancreatic acinar cells, lipase is found commonly stipulate the presence of two of the three following in the gastrointestinal tract, including the oesophagus, duo- criteria: typical abdominal pain; characteristic computed tomog- denum, stomach and colon.7 Lipase has also been described in the raphy (CT) findings, and/or amylase and/or lipase levels of three liver, heart, lungs and leukocytes.7,8 Pancreatic lipase content is or more times the upper limit of normal (ULN).1 approximately 100 times that of the small intestine and liver, and The sensitivity and specificity of serum lipase for pancreatitis at the pancreas to serum lipase concentration gradient is close to a cut-off of three times the ULN range from 64% to 100% and 20 000.7 from 99% to 100%, respectively.2–5 In comparison, at the same In addition to pancreatitis, mild lipase elevations above the cut-off, the sensitivity and specificity of amylase range from 50% ULN may be seen in a wide range of conditions, including peptic to 78.6% and from 99% to 100%.2–5 Lipase provides increased ulcer disease and other hepatobiliary disorders.6 However, to the

authors’ knowledge, no previous study has systematically inclusion were independently assessed by two reviewers before a evaluated the aetiology of lipase levels of three or more times the final decision on study eligibility was made. ULN. Knowledge of the potential alternative causes of significantly Data collection raised lipase is essential for clinicians because such levels may be A standardized table was utilized in the process of extracting data erroneously interpreted as indicative of pancreatitis in some cases. from each article. The information collected from each study This is especially important as lipase is advocated as the preferred included: author(s); study year; city(s)/country(s) of study; test for the diagnosis of pancreatitis in various guidelines and number of patients in the series (including numbers with elevated much weight is given to levels that exceed the ULN by three or lipase, and numbers with lipase levels of three or more times the more times.1,9 ULN); normal ranges of lipase and amylase; mean peak lipase The literature was therefore reviewed for causes other than levels; mean peak amylase levels; evidence of pancreatitis in CT pancreatitis of lipase levels of three or more times the ULN. The and/or ultrasonography (US); presence of abdominal pain or ten- objective of this review is not to suggest an alternative ‘cut-off’ for derness; method(s) used to confirm diagnosis, and condition(s) raised lipase, but, rather, to alert the clinician to other potential associated with lipase levels of three or more times the ULN as cited causes of significant lipase elevation (i.e. levels of three or more in the article (Appendix). Obvious confounders, such as alcohol- times the ULN) in order to facilitate more accurate interpretation ism or renal failure, were noted. Individual patients in whom these and improve patient care. confounders coexisted with the cause under investigation were generally excluded, except in studies outlining renal failure or alcoholism as potential causes of significant lipase elevation. Materials and methods Causes of lipase of three or more times the ULN in each study Eligibility criteria were categorized as either (i) ‘probable’ or (ii) ‘possible’.These two The criteria for the inclusion of a study in this systematic review groups were defined according to: (i) the number of study(s) required the reporting article to have been published after 1985. supporting the cause of raised lipase; (ii) the strength of confirma- Lipase levels of three or more times the ULN were defined as tory evidence, such as cross-sectional imaging, laparotomy/ representing significant elevation. At least one patient must have surgical findings and/or specific serological or other tests; (iii) the clearly shown lipase levels of three or more times the ULN attrib- possibility of underlying subclinical pancreatitis based on the utable to a cause other than pancreatitis, except in exceptional mechanism in question, and/or (iv) the presence or absence of circumstances as outlined below. Review articles, conference other potential causes of raised lipase. abstracts and proceedings, and articles which made insufficient explanation for the lipase result(s) were excluded from data Formulation of results analysis. Qualitative items from each study, primarily representing different causes of lipase levels of three or more times the ULN, were synthesized and divided into four final groups: (i) reduced clear- Literature search ance or physiological causes; (ii) intra-abdominal pancreatic and Using the keywords ‘pancreatitis’,‘lipase’,‘amylase’ and ‘diagnosis’, non-pancreatic causes; (iii) critical illness, and (iv) other. Neither the MEDLINE and EMBASE databases were searched for relevant a quantitative analysis nor a formal meta-analysis could be con- articles published from 1985 to August 2013. Methods of lipase ducted as a result of the significant heterogeneity among the arti- determination were initially labour-intensive and technically dif- cles and because of the inclusion of case reports in the final ficult, and more precise and faster assays were developed in the analysis. This systematic review was completed in line with late 1980s; therefore, this study targeted articles published from PRISMA (preferred reporting items for systematic reviews and 10–12 1985 onwards. Additional searches were performed using meta-analyses) guidelines.13 MEDLINE and EMBASE based on manual checking of the refer- ence lists from all appropriate articles. Any further studies were Results included if they met the inclusion criteria. The process of study selection and exclusion is outlined in Fig. 1. Data from 58 studies were included in the final qualitative analysis Study selection from which probable causes other than pancreatitis for lipase Studies from the literature search were initially screened by levels of three or more times the ULN were drawn. reviewing article titles and abstracts. Studies were excluded if the Three of the 58 articles indicated potential associations with review of the abstract identified any of the relevant exclusion lipase levels of three or more times or close to three times the ULN criteria. When study inclusion based on article title and abstract without conclusive evidence (Table 1). Table 2 summarizes all was equivocal, the full text was reviewed and further screened for potential causes of lipase levels of three or more times the ULN inclusion and exclusion criteria. Articles deemed suitable for without associated pancreatitis, categorized into the four groups

Figure 1 Study selection process. ULN, upper limit of normal outlined above. The strength of evidence for each alternative cause ered as possible causes of lipase levels of three or more times the is also outlined in Table 2. ULN.11,14,17 Patients with these diagnoses in the respective series often had a normal pancreas on US and/or CT scanning, and a Alternative causes of lipase levels of three or more negative laparotomy when performed (Appendix). times the ULN Non-pathological pancreatic hyperenzymaemia is a more Reduced lipase clearance/physiological causes recently described phenomenon with good evidence as a cause of There is no correlation between the cause of acute kidney injury significant lipase elevation.18–22 It is characterized by the absence of (AKI) and raised lipase.14–16 identifiable pancreatic disease in the presence of elevated pancreatic enzyme levels.23 Intra-abdominal non-pancreatic and pancreatic Elevated lipase levels may also be seen post-endoscopic retro- causes (non-traumatic) grade cholangiopancreatography (ERCP), without any associated Hepatocellular carcinoma, bowel cancer with liver metastases and evidence of pancreatitis.24 Gottlieb et al. showed that lipase levels unspecified metastatic bowel and gastric cancer can all be consid- of 1000 units/l (normal range: 40–240 units/l) after ERCP had

Table 1 Possible other causes of lipase levels of three or more times lipase after the administration of the dipeptidyl peptidase-4 the upper limit of normal (ULN) (DPP-4) inhibitors, sitagliptin and saxagliptin, for the treatment Authors, Possible association(s) with lipase of three or of type 2 diabetes.35 None of these patients had clinical features of year more times the ULN pancreatitis and lipase levels normalized in most after drug with- Bokemeyer, IBD: three of 70 and three of 66 patients with UC drawal.35 Lobo et al. used intramuscular morphine (10 mg) and 200240 and CD, respectively, had lipase levels over twice the ULN; however, the potential number of prostigmine (1 mg) for the investigation of sphincter of Oddi patients with lipase levels of three or more times dysfunction (SOD).36 Surprisingly, both patients with proven the ULN is not explicitly recorded in the article SOD and healthy controls showed a lipase rise that sometimes Carroccio Coeliac disease: adults and children with coeliac exceeded three times the ULN.36 Provocation did not induce pain et al., disease had lipase elevations of, respectively, up 36 200641 to 2.5 and 2.1 times the ULN at disease diagnosis in any of the healthy controls. Heikius et al., IBD: serum lipase was elevated by up to 2.9 times 199942 the ULN Infection Yoffe et al. found that some asymptomatic patients with chronic hepatitis C virus (HCV) infection demonstrated lipase CD, Crohn's disease; IBD, inflammatory bowel disease; UC, ulcerative colitis. levels of three or more times the ULN; lipase levels often normalized in patients who responded to HCV therapy.37 Patients with human immunodeficiency virus (HIV) may also sometimes develop high lipase levels, although the contribution of the virus specificity of only 55% for pancreatitis.24 The existence of foci of alone to this abnormality is debatable and at best possible.38 Gas- pancreatitis cannot be disproved, however, and the clinical signifi- troenteritis is also a possible consideration in patients with cance of this lipase rise is uncertain. elevated lipase without pancreatitis, but more evidence is required.11,15 Lipase in critical illness Multi-trauma patients without head injury have been reported Miscellaneous causesSarcoidosis has been reported in a single case to have significant lipase elevations without strong radiological or as a possible cause of lipase levels of three or more times the 39 operative evidence for pancreatitis.8,11,25–27 Broadly, these patients ULN. This patient had no clinical or imaging features of pan- 39 have sustained blunt abdominal or pelvic trauma, in some cases creatitis. Coeliac disease and inflammatory bowel disease (IBD) with associated liver injury.8,11,25,27 However, it is very difficult were associated with lipase elevations that came close to but did 40–42 to disprove underlying subclinical pancreatitis in such patients, not reach three or more times the ULN (Table 1). and therefore multi-trauma cannot be thought of as a probable cause of lipase levels of three or more times the ULN without Discussion pancreatitis. Summary of evidence Some authors have also pointed to lipase elevations of three or This systematic, qualitative review has outlined a wide variety of more times the ULN in non-surgical intensive care unit (ICU) causes of lipase levels of three or more times the ULN with the patients with such diagnostic categories as septic shock and res- purpose of significantly aiding the clinician in his or her interpre- piratory failure; underlying pancreatitis remains a significant pos- tation of this result. Although the specificity of lipase testing for 25,26 sibility here (Table 3). pancreatitis at a cut-off of three or more times the ULN is >99%, it is essential for health care providers to understand other potential causes of this abnormality.2–5 Other causes of lipase levels of three or more As Table 2 shows, there are many potential causes other than times the ULN pancreatitis for the significant elevation of lipase levels. Reduced Diabetes Malloy et al. showed that a very small proportion of clearance of lipase from the circulation can occur with renal patients with asymptomatic type 2 diabetes had lipase levels of impairment or macrolipase formation. Lipase may also be three or more times the ULN; this may thus be a possible cause elevated as a result of other intra-abdominal pathologies arising of significant lipase elevation.28 from the stomach, bowel and hepatobiliary tract, and from neo- Abdominal pain is a common finding in diabetic ketoacidosis plastic disease. Diabetes, drugs and infection can also be respon- (DKA); however, in the studies outlined in Table 2,29–33 DKA sible for lipase levels of three or more times the ULN. patients with elevated lipase and abdominal pain rarely showed Table 3 explains the possible pathogeneses of some of these clinical and/or radiological pancreatitis (see also Appendix). causes of elevated serum lipase. Drugs Despite the association of chronic alcoholism with chronic pancreatitis, some authors have shown lipase levels of three or Data bias and study limitations more times the ULN in otherwise asymptomatic alcoholics.34 As a result of the heterogeneous nature of the studies included, Some patients also experienced significant abnormalities in serum and often insufficient and poorly comparable quantitative data,

Table 2 Summary of causes of significantly raised lipase without pancreatitis Categories of causes Strength of evidence: study type(s) and method(s) of diagnosis confirmation Reduced clearance/physiological

Renal impairment AKI: case series (×2), case–control study (×2); blood tests ± US, CT, laparotomy AKI8,14-16 CRF: case series (×1), case–control study (×1), cohort study (×1); blood tests ± US + CRF with or without haemodialysis or continuous ambulatory peritoneal dialysis11,49,50 ?others (NR) Macrolipase51-56 Macrolipase: case report (×6); blood tests ± US, CT, laparotomy, ERCP, urine amylase, Potential complexes: IgG, IgA, IgM, α-2-microglobulin urine lipase, chromatography, immunoprecipitation assays Potential associated conditions: coeliac disease, Crohn's disease, hypergammaglobulinaemia, liver cirrhosis, multiple myeloma, systemic lupus erythematosus Intra-abdominal pancreatic and non-pancreatic (non-traumatic)

Hepatobiliary Biliary atresia: case series; blood tests + US ± MRI Biliary atresia57 Cholecystitis: case series (×2), case–control study (×2); blood tests ± US, CT, Cholecystitis11,14,15,43 laparotomy Cholangitis15 Cholangitis: case–control study; blood tests ± US, CT, ?others (NR) Liver necrosis8 Liver necrosis: case–control study; blood tests ± US, CT, laparotomy ?Post-ERCPa24 Post-ERCP: case series; blood tests Gastroduodenal Gastric perforation: case report; blood tests + CT, laparotomy Gastric perforation58 Peptic ulcer disease: case series (×2), case–control study (×1), cohort study (×2); blood Peptic ulcer disease with or without perforation2,4,5,14,43 tests ± US, CT, MRCP, ERCP, endoscopy, laparotomy Bowel Bowel necrosis/perforation: case–control study (×2); blood tests ± US, CT, laparotomy Bowel necrosis and/or perforation8,15 Bowel obstruction: case report (×1), case–control study (×1), cohort study (×1); blood Bowel obstruction2,15,59 tests ± US, CT, MRCP, ERCP, laparotomy Neoplasms Acinar cell carcinoma: case report (×1), case series (×2); blood tests ± US, CT, biopsy, Acinar cell carcinoma of pancreas60-62 laparotomy Others: ?hepatocellular carcinoma, ?metastatic bowel cancer, ?metastatic gastric Other neoplasms: case series with <10 patients (×1), case series (×1), case–control cancer, ?othersa11,14,17 study (×1); blood tests ± US, CT, laparotomy Non-neoplastic, pancreatic Non-pathological pancreatic hyperenzymaemia:– observational study/case series (×4), Non-pathological pancreatic hyperenzymaemia18-22 cohort study (×1); blood tests ± US, CT, MRI (including MRCP and MRCP-S), ERCP, Pancreas transplant rejection63 secretin-cerulein test, urine amylase Pancreas transplant rejection: case series; blood tests + pancreatic biopsy Other Ruptured AAA: cohort study; blood tests ± US, CT, MRCP, ERCP Ruptured AAA2 Haemorrhage from other sources: case report (×2); blood tests ± US, CT, laparotomy Intra-abdominal haemorrhage from other sources – ruptured ectopic pregnancy, Peritonitis: case–control study; blood tests + ?others (NR) ruptured ovarian cyst, ?others64,65 Peritonitis11 Critical illness

Neurosurgical ICH: observational study/case series (×2), case–control study (×3); blood tests ± US, CT, ICH with or without craniotomy8,25,66-68 craniotomy TBI/head injury without intracranial haemorrhage25,67,69 TBI:– observational study/case series (×1), case–control study (×1), cohort study (×1); blood tests ± US, CT, craniotomy ?Other critically ill/intensive care unit patients, including those with multi-system See text and Appendix traumaa25-27,67,68 Other

Diabetes Type 1 DM: case series (×1), cohort study (×1); blood tests ± ?others (NR) Type 1 DM (insulin-dependent diabetes mellitus)14,70 DKA: case series with <10 patients (×1), case series (×1), cohort study (×3); blood tests DKA (adults and children)29-33 ± CT, other imaging (not specified) ?Type 2 DM28 Type 2 DM: case–control study; blood tests + ?others (NR) Drugs Chronic alcoholism: case–control study; blood tests + ?others (NR) Alcohol (chronic alcoholism)34 Morphine + prostigmine provocation: cohort study; blood tests + CT, ERCP, HIDA scan Morphine + prostigmine provocation (in healthy controls and sphincter of Oddi Sorafenib: case series; method of diagnosis confirmation NR dysfunction)36 Nilotinib: case series; blood tests + ?others (NR) ?Sorafenib71 DPP-4 inhibitors: cohort study; blood tests only ?Nilotinib72 ?DPP-4 inhibitors (sitagliptin and saxagliptin)35 ?Others

Infection HCV: case–control study; blood tests ± US HCV37 HIV: observational study; blood tests ± US, CT ? HIV38 Gastroenteritis: case–control study (×2); blood tests ± US, CT, ?others (NR) ?Gastroenteritis11,15 CMV: case–control study; blood tests + ?others (NR) ?Others (e.g. ? CMV)11

Miscellaneous Sarcoidosis: case report; blood tests + US, CT, ERCP, gel filtration chromatography, liver ?Sarcoidosis39 biopsy ?Renal transplant rejection11 Renal transplant rejection: case–control study; blood tests + ?others (NR) aSee text. Possible causes of significantly raised lipase, as defined in the Methods section, are denoted by a preceding ‘?’. ‘Blood tests’ as one method of confirming a diagnosis implies the use of standard accepted serological tests for each respective condition (if applicable). Clinical assessment is by implication a part of diagnosis confirmation, and is thus not explicitly mentioned. AAA, abdominal aortic aneurysm; AKI, acute kidney injury; CMV, cytomegalovirus; CRF, chronic renal failure; CT, computed tomography; DKA, diabetic ketoacidosis; DM, diabetes mellitus; DPP-4, dipeptidyl peptidase-4; ERCP, endoscopic retrograde cholangiopancreatography; HCV, hepatitis C virus; HIDA, hepatobiliary iminodiacetic acid; HIV, human immunodeficiency virus; ICH, intracranial haemorrhage; Ig, immunoglobulin; MRCP, magnetic resonance cholangiopancreatography; MRCP-S, secretin-enhanced MRCP; MRI, magnetic resonance imaging; NR, not recorded; TBI, traumatic brain injury; US, ultrasonography.

Table 3 Possible pathogeneses of alternative causes of significantly raised lipase Reduced clearance/physiological Renal impairment • Lipase handling and metabolism: glomerular filtration is primarily responsible for the removal of lipase from the serum; the majority of lipase is then reabsorbed by renal tubules with subsequent intra-renal degradation.7,43,73 Liver, lungs and spleen also likely involved in lipase metabolism7,74 • Raised lipase in renal impairment: reduced glomerular filtration at least partially explains this.50 Other mechanisms also seem to exist as lipase levels in individuals do not correlate well with changing renal function75 • Haemodialysis and CRF patients: additional possibilities include subclinical foci of pancreatitis and increased lipase reabsorption in the intestine49,50 Macrolipase • Enlarged lipase molecule: may artificially elevate serum lipase measurements caused by reduced renal filtration53,54 • Presence of macrolipase may sometimes indicate an increased risk for associated disorders, such as autoimmune or lymphoproliferative disease51,52 Intra-abdominal pancreatic and non-pancreatic causes (other than pancreatitis) • Inflammation: pancreas probably highly sensitive to inflammation in adjacent organs/structures, such as the biliary tract and gastrointestinal tract, with subsequent increases in serum lipase caused by inflammation of these organs11,43 • Obstruction: biliary regurgitation into the pancreas from distal obstruction may induce pancreatic inflammation; biliary, pancreatic duct or bowel obstruction may also cause increased bloodstream diffusion of pancreatic enzymes4,11,14 • Alternative sources of lipase: stomach, small bowel, liver, gallbladder and other surrounding organs may potentially act as non-pancreatic sources of lipolytic enzymes14 • Peritonitis: mechanisms not clear with regards to peritoneal irritation (e.g. intra-abdominal haemorrhage) and elevated serum lipase65 • Impaired hepatic function: reduced hepatic metabolism of lipase may occur with impaired hepatic function (e.g. chronic liver diseases like biliary atresia)57,74 • Neoplasia: lipase elevation may be related to biliary or pancreatic ductal obstruction, formation of macrolipases, or (functional) tumour mass lipase production/hypersecretion17,60,62 • Non-pathological pancreatic hyperenzymaemia: mechanisms not yet characterized, although a genetic basis should be entertained23 Critical illness • ICU patients with critical illness/multi-organ failure: pancreatic hypoperfusion with cellular stress may be responsible for lipase elevations;25 alternatively, pancreatic enzymes in the gut may enter the submucosa and subsequently the systemic circulation during times of gut ischaemia from reduced splanchnic flow25,26 • Neurosurgical patients with severe head injuries: exocrine pancreatic enzyme production may be activated through central pathways, such as increased vagal tone, altered adrenergic stimulation, and/or release of activating hormones such as cholecystokinin66,68 Some alternative causes Diabetic ketoacidosis and type I DM • Possible causes of raised lipase in DKA: may include relative renal hypoperfusion and thus reduced serum clearance of the enzyme;30 alternatively, impaired pancreatic and/or splanchnic flow, in addition to non-pancreatic release of lipolytic enzymes, may be contributing factors.17,54,56 • In DKA and recent-onset type 1 DM in general: inflammation from immune-mediated β-cell destruction could potentially ‘spill over’ into the exocrine pancreas, with subsequent acinar cell damage14,30,70

CRF, chronic renal failure; DKA, diabetic ketoacidosis; DM, diabetes mellitus; ICU, intensive care unit.

quantitative analyses were not performed here. Some of the Lipase assays proposed causes of lipase levels of three or more times the It is important for clinicians to understand that assay interference ULN are at best speculative, but every effort has been made to and the detection of non-pancreatic lipases is possible; this in include only those causes for which there are plausible mecha- itself will not usually produce levels of three or more times the nism(s) and for which there exists evidence from multiple ULN, but can definitely alter lipase results.7,47 Demanet et al., for sources. An attempt was made in the data collection process to example, showed large increases in serum lipase after the admin- account for underlying conditions that may confound lipase istration of i.v. heparin to patients; the Ektachem and Wako assays values, such as alcoholism and the presence of renal impairment. were used in this study.48 When assay interference is suspected, Although the methods by which diagnoses were confirmed were clinicians should contact their clinical chemistry laboratory for recorded, there will inevitably be cases in which underlying clarification. mild pancreatic inflammation may have been missed in the respective studies; this is especially likely in retrospective series.15 Implications and future perspectives Normal findings in CT, ERCP, US and even laparotomy may Lipase remains a good serological test for the diagnosis of pan- not always preclude histological pancreatitis.43–45 Indeed, the CT creatitis. However, as shown by this study, levels of three or more scan may be normal in up to 25% of patients with clinical times the ULN do not automatically confirm the diagnosis and pancreatitis.30,46 many possible differential diagnoses exist. The diagnosis of

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Appendix Study data

Author(s), Hospital, country Patients in series and Normal Normal Peak amylase level Peak lipase level Imaging Presence of year Type of study patients with raised range range of (non-pancreatitis), (non-pancreatitis), (CT ± others) abdominal pain/ lipase levels, n of lipase amylase mean (range) mean (range) tenderness

Akaza et al., Fukuoka, Osaka, 129 NR NR NR NR NR 0/73 patients 200771 Sapporo, Tsukuba 73 had ↑ lipase w/o with ↑ lipase and Tokyo, Japan pancreatitis Prospective 8 had levels >5 × ULN, non-randomized and 32 had levels open label study >2–5 × ULN Argiris et al., New York, USA 86 10–70 U/l 25–125 U/l 117 (range 56 (range 9–482) No US or CT features 5/86 patients 199938 Prospective 26 had ↑ lipase w/o 17–806) of pancreatitis in with ↑ lipase observational study pancreatitis 6 patients with ↑ (epigastric Number with lipase lipase; 1 patient discomfort or levels ≥ 3 × ULN NR had mild pancreatic dyspepsia) duct dilatation and (pancreatitis ‘minimal pancreatic was not enlargement;’ suspected) imaging not performed in others due to no clinical suspicion Ashley & Boston, USA 1 NR NR 42 1614 No CT, US or MRI Nil Lauwers, Case report Had lipase level ≥ 3 × features of 200260 ULN pancreatitis Asvesta Thessaloniki, Greece 168 0–160 U/l NR NR 366 (79 in NR 0/168 patients et al., Case–control study 72 had ↑ lipase controls) with ↑ lipase 198834 At least 10 had lipase levels ≥ 3 × ULN Bokemeyer, Minden, Germany 136 0–60 U/l 28–100 U/l NR (1 patient had NR No US features of 0/19 patients 200240 Prospective 19 had ↑ lipase w/o levels > 2 × pancreatitis in all with ↑ lipase observational study pancreatitis (11 had ULN) 19 patients with ↑ CD, 8 had UC) lipase 6 had lipase levels >2 × ULN w/o pancreatitis Brooks et al., Cleveland, USA 1 12–70 U/l 0–137 U/l 1241 2664 No CT features of Yes (epigastric 200959 Case report Had lipase level ≥ 3 × pancreatitis pain) ULN

Carroccio Palermo, Italy 202 (90 adults, 112 20–270 IU/l 10–160 IU/l 240 (median) 432 (median) No US features of 10/90 adults and et al., Prospective children) (adults); (adults); (adults); 1.4 × (adults); 1.3 × pancreatitis in all 9/112 children 200641 observational study 19 adults and 21 variable for variable for ULN (median) ULN (median) 202 patients (‘recurrent children had ↑ lipase children children (children) (children) abdominal w/o pancreatitis pain’) No patient had lipase levels ≥ 3 × ULN (peak was 2.5 × ULN)

Catton & Nottingham, UK 1 23–300 IU/l 30–110 IU/l 380 4398 No CT features of Yes (epigastric Lobo, Case report Had lipase level ≥ 3 × pancreatitis pain) 201058 ULN Chase et al., Chattanooga, USA 306 5–208 U/l 30–110 U/l N/Ad (maximum N/Ad (maximum NR 26/26 patients 199643 Retrospective case 208 had non-pancreatic 385) 3685) with ↑ lipase series abdominal pain 26/208 had ↑ lipase 4 had lipase levels ≥ 3 × ULN

Chen et al., Taipei, Taiwan 84 <190 U/l <180 IU/l 127 ± 17 206 ± 35 No US features of 0/22 patients 199649 Retrospective case 22 had ↑ lipase w/o (haemodialysis (haemodialysis pancreatitis in all with ↑ lipase series pancreatitis patients); 192.1 patients); 146.1 22 patients with ↑ 4 had levels ≥ 3 × ULN ± 24.5 (no ± 18.4 (no lipase w/o pancreatitis dialysis) dialysis) Denz et al., Berlin, Mannheim and 66 <150 U/l NR NR NR CT showed features NR 200725 Karlsruhe, Germany 52 had ↑ lipase of pancreatitis in Prospective 38 had lipase levels ≥ 3 7/20 patients in observational study × ULN which it was done; No CT features of pancreatitis in 13 patients with lipase ≥ 3 × ULNbb

Diani et al., Pavia and Varese, 4 8–57 U/l NR Within normal 197 (patient 1); No US features NR 199817 Italy All 4 had ↑ lipase w/o limits (all 120 (patient 2); negative of Retrospective case pancreatitis patients) 351 (patient 3); pancreatitis in all series 3 had lipase levels ≥ 3 412 (patient 4) patients; no CT × ULN w/o features of pancreatitis pancreatitis in at least 2 patients Duerksen Winnipeg, Canada 1 <190 IU/l <120 IU/l 350 2000 No CT or US features Nil et al., Case report Had lipase level ≥ 3 × of pancreatitis 200039 ULN Frank & Landshut, Germany; 25 40–240 U/l 25–115 U/l N/Ad N/Ad NR 19/25 patients Gottlieb, Indianapolis, USA All 25 had ↑ lipase with ↑ lipase 199914 Retrospective case All 25 had lipase levels series ≥ 3 × ULN Gomez et al., Nottingham, UK 2979 0–300 U/l 0–100 U/l NR NR No CT features of 18/18 patients 20122 Retrospective cohort 18 had lipase levels ≥ 3 pancreatitis in all (acute study × ULN w/o 18 patients abdominal pancreatitisi pain) Goto et al., Akita and Matsumoto, 1 29–220 IU/l 115–360 IU/l 625 3338 No US features of Nil 200051 Japan Had lipase level ≥ 3 × pancreatitis Case report ULN Gottlieb Indianapolis, USA 231 40–240 U/l 25–115 U/l 200 ± 13 (cf. 657 2444 ± 288 (cf. NR 70/193 patients et al., Prospective case Number with ↑ lipase ± 104 for 9879 ± 1480 w/o 199624 series NR pancreatitis for pancreatitis pancreatitis 193 patients did not patients) patients) had abdominal have pancreatitis pain Gullo, 199618 Bologna, Italy 18 24–270 IU/l 0–220 IU/l NR (range NR (range No CT or US (×2) 0/18 patients Prospective case All 18 had ↑ lipase 1.4–4.1 × ULN) 1.5–7.7 × ULN) features of series At least 6 had lipase pancreatitis in all levels ≥ 3 × ULN patients Gullo, 200019 Bologna, Italy 102j 24–270 IU/l 0–220 IU/l NR (range NR (range 1.6–18 No US features of 0/19 patients Prospective 19 had ↑ lipase w/o 1.3–5.2 × ULN) × ULN) pancreatitis in all with ↑ lipase observational study pancreatitis 19 patients with ↑ 7 had lipase levels ≥ 3 lipase × ULN w/o pancreatitis Gullo et al., Bologna, Italy 18w 13–60 IU/l 13–53 IU/l NR (range NR (range No US, CT or MRI 0/18 patients 200620 Prospective 16 had ↑ lipase w/o (pancreatic ∼0.8–3.9 × ∼0.8–6.4 × features of observational study pancreatitis isoamylase) ULN) ULN) pancreatitis in all 7 had lipase levels ≥ 3 (pancreatic patients × ULN w/o isoamylase) pancreatitis Gullo, 200721 Bologna, Italy 42w 13–60 IU/l 28–110 IU/l NR 255 (mean of No US or CT features 0/42 patients Prospective 38 had ↑ lipase w/o peak levels in of pancreatitis in all observational study pancreatitis each patient patients; No MRI 30 had lipase levels ≥ 3 over 5 days) features of × ULN w/o pancreatitis in pancreatitis at some 36 patients point during study

Gumaste New York, USA 170 (95 w/o 31–213 U/l ?40–100 U/l N/Ad N/Ad NRf 95/95 patients et al., Prospective cohort pancreatitis + 75 with w/o 19934 study pancreatitis) pancreatitis 10 had ↑ lipase w/o (acute pancreatitis abdominal 1 had lipase levels ≥ 3 pain) × ULN w/o pancreatitis

Haddad Indianapolis, USA 50 15–120 U/l 25–115 U/l 162 ± 152 in 404 ± 385 in CT features of 36/50x patients et al., Prospective cohort 20 had ↑ lipase w/o (vitros); (vitros); DKA patients DKA patients pancreatitis in 1 (abdominal 200429 study pancreatitis 5–51 U/l 25–115 U/l with ↑ lipase or with ↑ lipase or patient (performed pain and/or 7 had lipase levels ≥ 3 (colorimetric) (Catachem) amylase (cf. 38 amylase (cf. 46 in 3 patients with vomiting) × ULN w/o ± 10 for DKA ± 27 for DKA lipase ≥ 3 × ULN) pancreatitis patients with patients with normal normal enzymes) enzymes)

Heikius Oulu, Finland 237aa <160 U/l 70–300 U/l 176 (range 66 (range 1.1–2.9 US showed NR et al., Prospective 16 had ↑ lipase w/o 1.1–1.9 × ULN) × ULN) increased/patchy 199942 observational study pancreatitis echogenicity of the No patient had lipase pancreas in 6/38 levels ≥ 3 × ULN patients with ↑ (peak was 2.9 × ULN) lipase or amylase Justice et al., Savannah, USA 38 (37 w/o pancreatitis 23–208 U/l 30–110 U/l 140 ± 109 712 ± 614 No CT features of NR 199466 Prospective case + 1 with pancreatitis) pancreatitis in the series 24 had ↑ lipase w/o 3 patients it was pancreatitis performed in Number with lipase levels ≥ 3 × ULN NR Keating & St Louis, USA 1 20–200 U/l 15–130 U/l 1143 (range 1139 (range No CT or US (×2) Yes (lower Lowe, Case report Had lipase level ≥ 3 × 119–1143 over 694–3095 over features of abdominal 200252 ULN 2 months) 2 months) pancreatitisg cramps) Klassen Baltimore, USA 69 (68 w/o pancreatitis 23–208 IU/l 30–110 U/l 341 ± 40 1548 ± 222 NR NR et al., Prospective case + 1 with pancreatitis) 199663 series Number with ↑ lipase NR Klimstra New Haven and 28 0–1 Teitz units NR NR NR (maximum 20 NR NR et al., Washington, USA 4 had ↑ lipase Teitz units) 199261 Retrospective case At least 1 had lipase series levels ≥ 3 × ULN Lando et al., Alexandria and 90 ∼60–65 U/l NR NR (maximum NR (maximum No imaging done 0/90 patients 201235 Washington, USA 31 had ↑ lipase w/o (ULN)h was 100 U/l 453) (patients Retrospective cohort pancreatitis above normal) asymptomatic) study Number with lipase levels ≥ 3 × ULN NRh Lee et al., Taipei, Taiwan 89 ≤200 U/l ≤190 U/l NRt NRt See footnoteu Difficult to 201067 Case–control study 43 had ↑ lipase or assess/NRv amylase (exact number with ↑ lipase NR) Liu et al., Chicago, USA 75 0–55 U/l 0–125 U/l 402 474 US done in 3/11 0/11 patients 200168 Case–control study 11 had ↑ lipase and patients with ↑ with ↑ lipasek amylase levels lipase, US + CT Number with lipase done in 3/11 levels ≥ 3 × ULN NR patients; nil imaging in 5 patients – no US or CT features of pancreatitis in these patients Lobo et al., Nottingham, UK 44 (20 controls + 24 23–300 U/l 30–110 U/l ∼7 × ULN (in ∼10 × ULN NR 0/20 controls 200736 Prospective cohort patients with SOD) controls, (median – in (post-provocation); study At least 17 controls and post-provocation controls, 20/24 SOD 23 SOD patients had with morphine post-provocation patients ↑ lipase levels and with morphine (post-provocation) Exact number with prostigmine) and lipase levels ≥ 3 × prostigmine); ULN NR levels increased up to 50 × ULN in SOD patients (exact values NR) Lott et al., Columbus, USA 156 Variablee Variablee N/Ad N/Ad NR NR 198611 Case–control study Up to 39 patients had lipase levels ≥ 3 × ULN w/o pancreatitise Lott & Lu, Columbus, USA 100 <200 U/l <140 U/l N/Ad N/Ad NR NR 19918 Case–control study Exact number with ↑ lipase NR At least 6 patients had lipase ≥ 3 × ULN w/o pancreatitis Malloy et al., San Diego, USA 1869 0–60 U/l 13–53 IU/l 28 ± 20 (type 2 42 ± 29 (type 2 NR 0/119 patients 201228 Case–control study 119 type 2 DM patients (pancreatic DM, DM, with ↑ lipase and 29 obese amylase) screening), 27 screening), 43 non-DM patients had ± 16 (type 2 ± 33 (type 2 ↑ lipase w/o DM, baseline); DM, baseline); pancreatitis 26 ± 10 33 ± 26 13 type 2 DM patients (obese, (obese, and 2 obese non-DM screening), 26 screening), 33 patients had lipase ± 10 (obese, ± 14 (obese, levels ≥ 3 × ULN w/o baseline) baseline) pancreatitiss

Manjuck NY, USA 245 23–208 U/l NR 140 (cf. 389 for 900 (cf. 2231 for US features of Difficult to et al., Prospective cohort 99 had ↑ lipase (11/99 patients with patients with pancreatitis present assessc 200526 study had pancreatitis) image-proven image-proven in 2 patients; CT Number with lipase pancreatitis)b pancreatitis)b features of levels ≥ 3 × ULN NR pancreatitis present in a further 9 patientsa Masoero Torino, Italy 212 (63 with CRF, 98 23–300 U/l 0–200 U/l 390 ± 336 in HD 389 ± 347 in HD US done in 40 0/212 patients et al., Prospective cohort on HD, 28 on CAPD, patients; 280 ± patients; 292 ± patients with 199650 study 23 with renal 128 in CRF 211 in CRF particularly high transplants) patients; 255 ± patients; 259 ± pancreatic enzyme 118 had ↑ lipase levels 109 in CAPD 177 in CAPD levels – no US 13 had lipase levels ≥ 3 patients; 209 ± patients; 175 ± features of × ULN (10 HD, 1 93 in RT 77 in RT pancreatitis in CAPD, 2 CRF) patients; 148 ± patients; 122 ± these patients 64 in controls 62 in controls Matos et al., Indianapolis and 17 NR NR NR NR (maximum NR 10/17 had 200962 Nashville, USA; 4 had ↑ lipase levels 4151) abdominal pain Mannheim and w/o pancreatitis (unclear if Dresden, Germany Number with lipase ≥ 3 same as those Retrospective case × ULN NR patients with ↑ series lipase) Mitura & Siedlce, Poland 1 13–60 IU/l 28–100 IU/l 2113 3184 No US features of Yes Romanczuk, Case report Had lipase level ≥ 3 × pancreatitis (CT not (para-umbilical 200964 ULN done) pain) Nair et al., New York, USA 100 0–72 IU/l 0–330 IU/l NR NR CT done in the 17 27/100 patients 200030 Prospective case 20 had ↑ lipase w/o patients with lipase (number with ↑ series pancreatitis levels ≥ 3 × ULN – lipase and 17 had lipase levels ≥ 3 8/17 had CT abdominal pain × ULN; of these, 9 features of NR) did not have pancreatitis pancreatitis Nsien et al., Washington, USA 3 23–208 IU/l 20–150 IU/l 497 ∼3200 No CT features of 0/3 patientsl 199231 Retrospective case All 3 had lipase levels ≥ pancreatitis in any series 3 × ULN patient Okumura Otsu, Japan 1 5–160 IU/l 25–80 IU/l 73 1730 No CT or US features Yes (NB lipase et al., Case report Had lipase level ≥ 3 × of pancreatitis measured 199853 ULN during Crohn's disease relapse) Pezzilli et al., Bologna, Italy 88 24–270 IU/l 0–220 IU/l NR (range NR (range 5–826) No US features of 0/6 patients with 199769 Prospective cohort 6 had ↑ lipase 22–728) pancreatitis in all ↑ lipase study 1 had lipase levels ≥ 3 6 patients with ↑ × ULN lipase Quiros et al., Davis, Aurora and 67 13–51 U/l 30–140 U/l 136 ± 295 94 ± 163 No imaging was done 42/67 patients 200832 Stanford, USA 21 had ↑ lipase w/o (upon Prospective cohort pancreatitis; 14 of presentation); study these had abdo pain, 14/21 patients and 7 did not) with ↑ lipase Number with lipase ≥ 3 × ULN NR Rosti et al., Bergamo, Bologna, 73 NR NR NR NR NR 0/21 patients 200972 Brescia, Catania, 21 had ↑ lipase w/o with ↑ lipase Catanzaro, Naples, pancreatitis Rome, Turin and 3 had lipase levels > 5 Udine, Italy × ULN w/o Prospective case pancreatitis series Ryan et al., Iowa, USA 100 <190 U/l <170 U/l 544 ± 112 in 716 ± 150 in No CT features of 5/17 patients 199427 Prospective cohort 17 had ↑ lipase (5 of patients w/o patients w/o pancreatitis in the with ↑ lipasez study these had clinical pancreatitis pancreatitis 17 patients with ↑ pancreatitis) (but raised (but raised lipase; US features Number with lipase ≥ 3 enzymes) cf. enzymes) cf. of pancreatitis in × ULN NR 725 ± 202 in 882 ± 349 in 1/17 patients with patients with patients with ↑ lipasey clinical clinical pancreatitis pancreatitis Semakula Bonheiden, Brussels, 307 0–9 years: 15–97 U/l 47 ± 21 (range 88 (range NR NR et al., Ghent and Liege, Numbers with ↑ lipase 17–136 U/l; NR) 12–4,177) 199670 Belgium; NR) 10–19 years: Stockholm, 30–167 U/l; Sweden 20–39 years: Prospective cohort 46–235 U/l study

Sinha et al., London and 1 5–65 IU/l 25–125 IU/l 1121 1700 No CT features of Yes (epigastric, 201065 Southend-on-Sea, Had lipase level ≥ 3 × pancreatitis then UK ULN generalized) Case report

Smith et al., Sydney, Australia 1880 <190 U/l 27–100 U/l <100 (median) 190–285 (median) NR NR 200515 Case–control study 427 had ↑ lipase w/o pancreatitisr 62 had lipase levels ≥ 3 × ULN w/o pancreatitis Sutton et al., Nottingham, UK 1520 <300 IU/l <110 IU/l NR NR NR NR 20095 Case–control study Number with ↑ lipase NR 41 had lipase levels ≥ 3 × ULN w/o pancreatitis Taes et al., Ghent, Belgium; 1 23–300 U/l 30–110 U/l ∼300 3764 No CT features of Yes (patient 200054 Columbus, USA Had lipase level ≥ 3 × pancreatitis (ERCP initially Case report ULN showed minimal admitted with dilation of chronic choledochus and constipation Wirsung duct) and progressive abdominal distension with lipase of 575) Testoni et al., Milan, Italy 25 0–60 IU/l 13–53 IU/l NR (range NR (range 0/25 had US, CT or 0/25 patients 200922 Prospective cohort 11 had ↑ lipase (pancreatic 76–227) 65–364) MRCP features of study Number with levels ≥ 3 amylase) pancreatitis; 2/25 × ULN NR had MRCP features of chronic pancreatitis; 8/25 had MRCP-S features of chronic pancreatitis Vantyghem Lille, France 164 (52 had DKA, 90 0–190 IU/l 0–160 IU/l 194 ± 270 (in 348 ± 690 (in NRn NRo et al., Prospective cohort had poorly-controlled DKA group) DKA group) 199933 study DM, 22 had well-controlled DM, 27 were controls) 31 had ↑ lipase w/o pancreatitis (19/52 patients with DKA had ↑ lipasem); Number with lipase levels ≥ 3 × ULN NR Wen et al., Taipei, Taiwan 37 <120 U/l <100 U/l NR (although no NR 0/37 had US features 0/37 patientsq 200557 Prospective case 12 had ↑ lipase w/o child had levels of pancreatitis; series pancreatitis ≥ 3 × ULN) 18/31 patients with 5 had levels ≥ 3 × ULN BA underwent MRI w/o pancreatitis and did not have any features of pancreatitis Yoffe et al., Houston, USA 103 114–286 U/l 25–115 U/l 82 ± 30 (cf. 75 ± 253 ± 72 (cf. 210 NRp 0/103 patients 200337 Case–control study 26 had ↑ lipase w/o 45 for controls) ± 42 for pancreatitis; controls) Number with lipase levels ≥3 × ULN NR

Yuki et al., Izumo, Japan 1 0–50 IU/l 50–170 IU/l Peak NR (but > 888 No US or CT features Nil 199955 Case report Had lipase level ≥ 3 × ULN) of pancreatitis ULN

Zachee Antwerp, Belgium 40 NR NR 4.6 ± 3.1 × ULN 3.5 ± 3.9 × ULN NR 0/37 patients w/o et al., Prospective case 26 had ↑ lipase levels (w/o (w/o pancreatitis 198516 series (3 of these patients pancreatitis) pancreatitis) had pancreatitis) Number with lipase levels ≥ 3 × ULN NR

Zaman et al., Leuven, Belgium 1 23–208 U/l 30–85 U/l 1104 2600 NR NR 199456 Case report Had lipase level ≥ 3 × ULN aImaging performed in a total of 50 patients with elevated lipase levels. bMaximum mean amylase or lipase levels in the 39 of 50 patients with elevated lipase who underwent imaging but showed no radiologic features of pancreatitis. cThe majority of patients with elevated lipase levels were intubated and sedated, and thus clinical features (e.g. abdominal tenderness) were hard to ascertain. dMean for elevated lipase or amylase not provided as study explored non-uniform sets of patients with multiple different diagnostic categories (e.g. patients with abdominal pain compared with patients with pancreatitis). eExact number cannot be expressed as four different methods of lipase determination and two different methods of amylase measurement were utilized; not all four methods of lipase measurement were always used in every patient; three to six of 14 patients with cholelithiasis and/or cholecystitis, four to 13 of 43 patients with inflammatory disorders of the biliary and gastrointestinal tract, two to five of 35 patients with complications of renal transplantation, two to seven of 17 patients with renal failure, and two to eight of 22 patients with accidental trauma had lipase levels of ≥3 × ULN. fIt is not specified whether any of the 10 patients with raised lipase underwent CT scanning; the three patients with biliary pathology had a normal pancreas. gOne abdominal CT scan, and two US scans were performed over a 2-month period. hExact value not recorded. iTen patients had a ruptured AAA, six had a perforated duodenal ulcer and two had intestinal obstruction. jDifferent patient subset from Gullo, 1996.18 kThe number of patients who were intubated/ventilated and/or had impaired sensorium (and thus would alter the reporting of abdominal pain or tenderness) was not reported in the article. lOne of these patients was confused and one was drowsy on admission, which may have made abdominal pain difficult to assess.

mNine of 52 DKA patients had chronic alcoholic pancreatitis with pancreatic calcifications, but not all patients with very high lipase levels in the DKA group had chronic pancreatitis. nAlthough the number of patients who underwent CT scanning/other imaging was not recorded, the number of patients with ‘pancreatic calcifications’ is recorded in the text. oAlthough the number of patients with abdominal pain was not recorded, the article text does state that ‘none of the [DKA] patients had clinical signs of acute pancreatitis’; this statement is not further elaborated in the text. pAlthough not recorded, those patients with lipase levels >2 × ULN were assessed by US. qAbdominal pain may have been difficult to assess in some patients as the patients were all children, with an age range of 4 months to 11.2 years (median: 2.4 years). rA diagnosis of severe pancreatitis was made in case of US or CT changes of acute pancreatitis; a diagnosis of indeterminate pancreatitis was made in case of abdominal pain consistent with pancreatitis but no CT or US features of the disease. sThis study looked at two separate groups that had been recruited for other large clinical trials: type 2 DM patients, and obese non-DM patients; lipase and pancreatic amylase levels were measured at the study screening period, then at baseline prior to commencement of the other trials. Note that by the time of randomization (i.e. at baseline), only two (of 13) and non (of two) type 2 DM and obese non-DM patients, respectively, still had lipase levels ≥ 3 × ULN. tAlthough there were no specific recordings for amylase and lipase levels in patients without pancreatitis compared with patients with pancreatitis, some important results were as follows: mean peak amylase and lipase levels in severe head injury were 460 ± 544 and 1027 ± 1643, respectively; in spontaneous ICH were 362 ± 253 and 854 ± 1143, respectively; in SAH and other vascular disease were 337 ± 256 and 552 ± 853, respectively; and in patients who had tumour bleeding during admission/operation were 341 ± 381 and 749 ± 972, respectively. With respect to the type of neurosurgical intervention, the highest lipase levels were seen upon aneurysm clipping or other neurovascular surgery (551 ± 825) and upon insertion of external ventricular drains, intracranial pressure monitors and/or ventriculoperitoneal shunts (547 ± 680). uFour of 14 patients with elevated amylase and/or lipase had an abnormal pancreas on US, and seven of 11 had an abnormal pancreas on CT; in total, CT and/or US scanning were performed in 34 patients (four patients underwent both US and CT scanning; in total nine patients were radiologically positive for pancreatitis). Indications for scanning were: symptoms/signs of pancreatitis, amylase >3 × ULN, lipase >5 × ULN, positive peritoneal signs, and/or fever of unknown origin. vAssessment made difficult by altered levels of consciousness in some/all patients. wUnclear if this patient subset was also included in the other studies by this author (Gullo).20,21 xOf the 29 DKA patients with normal pancreatic enzymes, data on abdominal pain and/or vomiting were available for only 21. yNo patient with persistently elevated amylase or lipase had CT features of pancreatitis; one patient had US features of pancreatitis; in total, five of 17 were clinically diagnosed as having pancreatitis. zFive of 17 patients were clinically diagnosed as having pancreatitis (despite normal CT scans) according to failed enteral feeding + concomitant raised pancreatic enzymes + abdominal distension + epigastric tenderness; one of these patients had a laparotomy. aaSeven of 237 patients at some point had pancreatitis (preceding onset of IBD in two, concomitant with onset of IBD in two, and after onset of IBD in three); two of these had raised pancreatic enzyme(s). bbCT scan was performed in patients with lipase >3 × ULN; although 38 patients had lipase higher than this threshold, 18 could not undergo imaging as a result of cardiopulmonary instability (n = 7), discharge from ICU prior to CT (n = 7), death (n = 3) and subsequent withdrawal of consent (n = 1). Seven of 20 had morphological alterations of the pancreas on CT (in one patient only a small fluid collection was detected at the pancreatic tail). AAA, abdominal aortic aneurysm; CAPD, continuous ambulatory peritoneal dialysis; CD, Crohn’s disease; CR, case report; CRF, chronic renal failure; CT, computed tomography; DKA, diabetic ketoacidosis; DM, diabetes mellitus; HD, haemodialysis; ICH, intracranial haemorrhage; MRCP, magnetic resonance cholangiopancreatography; MRCP-S, secretin-enhanced MRCP; MRI, magnetic resonance imaging; NR, not recorded; SAH, subarachnoid haemorrhage; SOD, sphincter of Oddi dysfunction; UC, ulcerative colitis; ULN, upper limit of normal; US, ultrasonography; w/o, without.