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Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia
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Digestive Endoscopy
Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia Milena Di Leo a , Maria Chiara Petrone b , Raffaella Alessia Zuppardo a , Giulia Martina Cavestro a , Paolo Giorgio Arcidiacono b , Pier Alberto Testoni a , Alberto Mariani b,∗ a Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy b Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
a r t i c l e
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Article history: Received 29 February 2016 Accepted 3 August 2016 Available online xxx Keywords: EUS MRCP Pancreas Secretin stimulation
a b s t r a c t Background: Magnetic resonance cholangio-pancreatography (MRCP) findings in people with chronic asymptomatic pancreatic hyperenzymemia (CAPH) have shifted the hypothesis that CAPH is always non-pathological. However, there have been no studies including both secretin-MRCP (S-MRCP) and endoscopic ultrasonography (EUS) to examine the pancreatic morphology in these subjects. Aim: To prospectively assess the diagnostic approach for CAPH using both pancreatic EUS and S-MRCP. Methods: In a case-control prospective study from January 2010 to December 2014, 68 consecutive subjects with CAPH were scheduled to undergo S-MRCP and EUS (CAPH group) in a tertiary care setting. In the same period, the EUS findings of this group were compared with 68 patients examined by EUS alone for submucosal lesions of the gastric fundus, matched for sex and age (control group). Results: EUS detected pancreatic alterations in 60.3% of the CAPH group and 13.2% of controls (p < 0.001). S-MRCP showed pancreatic alterations in 51.5% in the CAPH group. With the combined procedures, pancreatic abnormalities were detected in 63.3%. The diagnoses established by the two techniques were concordant in 51 (75%) of the 68 CAPH subjects; in the remaining 17 (25%) the two methods gave additional information. Conclusions: In people with CAPH S-MRCP and EUS are both recommended in order to detect pancreatic abnormalities before this biochemical alteration is confirmed as benign CAPH, or Gullo’s syndrome. © 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction Patients with no clinical symptoms occasionally present high serum concentrations of pancreatic enzymes. This condition is called “chronic asymptomatic pancreatic hyperenzymemia” [1] (CAPH) or Gullo’s syndrome [2] in honor of the first author to describe it. The syndrome is defined as chronic abnormally high plasma concentrations of pancreatic enzymes in asymptomatic patients with no evidence of pancreatic alterations. Since that first study, further characteristics have been clarified, such as a familial
∗ Corresponding author at: Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Via Olgettina 60, 20132 Milano, Italy. Fax: +39 2 26433491. E-mail address: [email protected] (A. Mariani).
form [3], and wide daily fluctuations in serum concentrations [4]¸ so the condition is considered benign. However, magnetic resonance cholangio-pancreatography (MRCP) examination of these people, with or without secretin stimulation [5–10], found pancreatic abnormalities such as pancreas divisum, early chronic pancreatitis, pancreatic cysts, intraductal pancreatic mucinous neoplasia (IPMN) and pancreatic tumors, or dysfunction of the sphincter of Oddi (SOD). These studies showed that abnormalities in the pancreatic ductal system and parenchyma could be found in up to half the people investigated. A significant proportion had clinical disease. These findings led to the hypothesis that CAPH may not always be benign and pancreatic imaging is indicated to exclude an underlying disease [11]. As yet no studies systematically including S-MRCP and EUS in the diagnostic investigation of CAPH have been reported. The aim of this prospective case-control study was to assess the diagnostic approach for people with CAPH, using EUS and S-MRCP.
http://dx.doi.org/10.1016/j.dld.2016.08.109 1590-8658/© 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
Please cite this article in press as: Di Leo M, et al. Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.08.109
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2. Materials and methods 2.1. Patient enrollment In the present case-control prospective study, over a five-year period, all consecutive persons with CAPH were scheduled to undergo S-MRCP and EUS in our center, according to a standard study protocol approved by the institutional review board. EUS findings of this CAPH group were compared to those of patients who had undergone EUS investigation in the same period for submucosal lesions of the gastric fundus, matched for sex and age (control group). S-MRCP was not done in the control group. CAPH was defined as asymptomatic high concentrations of serum amylase and lipase on at least three occasions in one year, with a normal pancreas at trans-abdominal ultrasonography and/or CT scan. The study was approved by the institutional ethics committee and run in accordance with criteria for Good Clinical Practice and the World Medical Association Declaration of Helsinki. Informed consent regarding study procedures and data management for scientific purposes was routinely obtained from all patients. 2.2. Exclusion criteria CAPH subjects were excluded if at least one of the following was found: (a) no informed consent; (b) under 18 years old; (c) pancreatic pain; (d) evidence of pancreatic pathology at previous radiological evaluation; (e) neoplasia; (f) contraindication to MRCP and/or EUS; (g) HBV or HCV infection; (h) renal insufficiency; (i) celiac diseases; (j) macroamylasemia or macrolipasemia; (k) high serum cholesterol or triglycerides; (l) endocrine or exocrine pancreatic insufficiency; (m) alcohol intake more than 60 g/day; (n) hyperenzymemia for less than 12 months; (o) previous surgery and/or endoscopy of the pancreas or the papilla of Vater; (p) pregnancy; (q) past surgical procedures that could impair complete visualization of the pancreas. Exclusion criteria in the control group were: (a) no informed consent; (b) under 18 years old; (c) alcohol intake more than 60 g/day; (d) evidence of pancreatic pathology; (e) pregnancy; (f) past surgical procedures that could impair complete visualization of the pancreas. 2.3. Clinical evaluation Demographic data, body mass index (BMI), daily alcohol consumption, smoking habit, and detailed clinical history were recorded for all study participants. In addition, at enrollment, fecal elastase levels were obtained for all CAPH cases (normal value 200 g/g [12,13]) and 50 of the most frequent CFTR gene mutations in populations of European origin (Kit Elucigene® CF-EU2v1, Delta Diagnostics, UK) were examined. 2.4. EUS EUS procedures were done by one experienced endosonographer (MCP, with more than 1000 EUS per year in the last five years). A linear-scanning echoendoscope (EG-3830UT, EG-3630U, FG36UX; Pentax, Hamburg, Germany) at 5–10 MHz was used. During procedures patients were deeply sedated with propofol (Diprivan® , AstraZeneca, Italy) infused with a TCI pump (Terufusion-TIVA/TCI TE372 Terumo Europe N.V., Leuven, Belgium) using the Marsh TCI model (DiprifusorTM AstraZeneca, Macclesfield, UK), under an anesthetist’s supervision. After completion of the examination for submucosal gastric lesions, the endosonographer carefully scanned the pancreas, looking at the head and tail from the proximal stomach and, after that, the body and the uncinate process from the duodenum. The EUS
diagnosis of chronic pancreatitis was based on Rosemont criteria [14]. In the CAPH group, EUS operator was blind respect to S-MRCP findings but it knew the disease of patient at the time of procedure. 2.5. MR cholangio-pancreatography with secretin MRCP was carried out using a 1.5 T magnet (Signa horizon; GE Medical Systems, Milwaukee, WI) and phased-array coils. Single-shot fast-spin echo, breath-hold, 2D, heavily T2-weighted images were employed. The following parameters were applied: ∞/800–1400; thickness 40–50 mm; matrix 256–512; field of view 35–40 cm; acquisition time 2 s. Patients took 200 mL of negative super-paramagnetic oral contrast agent (Lumirem; Guerbet, Aulnay-sous-Bois, France) before the imaging procedure. All patients examined by MRCP received an i.v. bolus injection of secretin (Secrelux; Goldham, Zusmarshausen, Germany; 1 IU/kg) to enhance the pancreatic ductal morphology. Ductal findings were evaluated according to the Cambridge classification and chronic pancreatitis was diagnosed and graded on the basis of the different abnormal ductal findings [15,16]. SOD was diagnosed if the main pancreatic duct diameter at the body 15 min after secretin stimulation was ≥1 mm larger than the basal value [17]. Although the outcome of CAPH is not an endpoint of the present study, we scheduled a follow-up in all CAPH subjects with abnormal findings at EUS or S-MRCP. 2.6. Statistical analysis Mean and standard deviation (SD) were used for continuous variables, percentages for categorical variables. Groups were compared using the Mann–Whitney test for continuous variables (on account of their non-normal distribution) and Yates corrected chi square test or Fisher’s test for categorical variables. Significance was set at p < 0.05 with two tails. Data were analyzed using the SPSS 21.0 system software (Chicago, IL, USA). 3. Results 3.1. Study population We enrolled 68 CAPH subjects and 68 controls from January 2010 to December 2014. Nine CAPH patients were excluded, three because of hepatic disease, two for celiac disease, one for renal insufficiency, two for contraindication to EUS and one to SMRCP. The two groups were homogeneous for all variables except cigarette smoking (Table 1). 3.2. EUS EUS pancreatic alterations were significantly more frequent in the CAPH than control group (60.3% and 13.2%; p < 0.001) (Table 2). This difference was mainly due to the higher frequency of signs of chronic pancreatitis in the CAPH group (32.4%) than in controls (4.4%) (p < 0.001). According to the Rosemont classification, there were significantly more people with EUS signs “suggestive of” and “consistent with” chronic pancreatitis in the CAPH group (Table 3). The persons with normal and abnormal EUS in the CAPH group were similar for both smoking and alcohol consumption, time elapsed from the first detection of pancreatic hyperenzymemia and EUS investigation, and serum lipase and amylase levels. CAPH subjects with normal EUS findings were significantly younger than those with abnormal EUS (Table 4). Among the EUS abnormalities in the CAPH group, the frequency of chronic pancreatitis and IPMN rose with quartiles of age more than in people with normal EUS (p = 0.02).
Please cite this article in press as: Di Leo M, et al. Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.08.109
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Table 1 Main demographic data and characteristics of study population.
Males [no. (%)] Age [mean (SD)] BMI [mean (SD)] Cigarette smoking Never [no. (%)] Previous [no. (%)] Active [no. (%)] Pack-years [mean (SD)] Alcohol consumption Never [no. (%)] Previous [no. (%)] Active [no. (%)] Alcohol/day [mean (SD)] g Duration of alcohol use [mean (SD)] yrs
Control group (n = 68)
CAPH group (n = 68)
37 (54.4%) 59.1 (14.4) 24.6 (3.5)
37 (54.4%) 57.1 (15.4) 23.7 (3.5)
p 1.000 0.466 0.215
38 (55.9) 3 (4.4) 27 (39.7) 17.4 (20.9)
51 (75.0) 11 (16.2) 6 (8.8) 7.8 (16.2)
<0.001
51 (75.0) 3 (4.4) 14 (20.6) 3.1 (6.2) 10.6 (20.1)
49 (72.1) 6 (8.8) 13 (19.1) 6.0 (15.2) 9.4 (16.9)
0.584
0.010
0.461 0.978
CAPH: chronic asymptomatic pancreatic hyperenzymemia; BMI: body mass index.
Table 2 EUS findings in the two groups.
Normal [no. (%)] Abnormalities [no. (%)] Pancreas divisum [no. (%)] IPMN [no. (%)] Main duct type [no. (%)] Branch type [no. (%)] Chronic pancreatitis [no. (%)] Pancreas divisum and chronic pancreatitis [no. (%)] NET and chronic pancreatitis [no. (%)]
Control group (n = 68)
CAPH group (n = 68)
p
59 (86.8) 9 (13.2) 1 (1.5) 5 (7.4) 0 5 3 (4.4) 0 0
27 (39.7) 41 (60.3) 9 (13.2) 10 (14.7) 1 9 19 (27.9) 2 (2.9) 1 (1.5)
< 0.001
<0.001
CAPH: chronic asymptomatic pancreatic hyperenzymemia; IPMN: intraductal papillary mucinous neoplasia; NET: neuroendocrine tumor.
Table 3 EUS diagnosis of chronic pancreatitis (CP) according to the Rosemont classification.
No CP [no. (%)] Other abnormality [no. (%)] Normal [no. (%)] Indeterminate for CP [no. (%)] CP [no. (%)] Suggestive of CP [no. (%)] Consistent with CP [no. (%)]
Control group (n = 68)
CAPH group (n = 68)
p
65 (95.6) 6 (8.8) 54 (79.4) 5 (7.4) 3 (4.4) 1 (1.5) 2 (2.9)
46 (67.6) 19 (27.9) 24 (35.3) 3 (4.4) 22 (32.4) 18 (26.5) 4 (5.9)
< 0.001
CAPH: chronic asymptomatic pancreatic hyperenzymemia; CP: chronic pancreatitis.
Table 4 Main demographic data of subjects in the CAPH group with normal or abnormal EUS.
Males [no. (%)] Age [mean (SD)] yrs BMI [mean (SD)] Cigarette smoking Never [no. (%)] Previous [no. (%)] Active [no. (%)] Pack-years [mean (SD)] Alcohol consumption Never [no. (%)] Previous [no. (%)] Active [no. (%)] Alcohol/day [mean (SD)] g Duration of alcohol use [mean (SD)] yrs Time from first detection of hyperenzymemia and EUS [mean (SD)] yrs Amylase × u.n.l.a (max) [mean (SD)] Lipase × u.n.l.a (max) [mean (SD)]
Normal EUS (n = 27)
Abnormal EUS (n = 41)
p
11 (40.7) 50.6 (16.8) 22.9 (3.8)
26 (63.4) 61.4 (12.8) 24.2 (3.2)
0.084 0.007 0.130
22 (81.5) 3 (11.1) 2 (7.4) 3.4 (9.4)
29 (70.7) 8 (19.5) 4 (7.4) 10.7 (19.1)
0.588
20 (74.1) 2 (7.4) 5 (18.5) 6.0 (18.3) 7.9 (15.8) 2.6 (1.8) 3.1 (1.8) 4.1 (2.3)
29 (70.7) 4 (9.8) 8 (19.5) 6.0 (13.0) 10.4 (17.8) 2.4 (2.3) 3.8 (5.3) 4.3 (4.8)
0.935
0.130
0.743 0.680 0.193 0.220 0.485
CAPH: chronic asymptomatic pancreatic hyperenzymemia; BMI: body mass index; EUS: endoscopic ultrasonography. a Number of times the upper normal limit (u.n.l.).
Please cite this article in press as: Di Leo M, et al. Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.08.109
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Table 5 S-MRCP (secretin-magnetic resonance cholangio-pancreatography) findings in 68 persons with CAPH.
Normal Abnormal Pancreas divisum IPMN Chronic pancreatitis SOD Cyst Pancreas divisum and chronic pancreatitis
Number
%
33 35 11 5 13 4 1 1
48.5 51.5 16.2 7.4 19.1 5.9 1.5 1.5
CAPH: chronic asymptomatic pancreatic hyperenzymemia; IPMN: intraductal papillary mucinous neoplasia; SOD: sphincter of Oddi dysfunction.
3.3. S-MRCP S-MRCP detected pancreatic abnormalities in 35 people in the CAPH group (51.5%) (Table 5).
3.4. Comparison of EUS and S-MRCP findings The comparison of normal and abnormal EUS and S-MRCP findings in CAPH subjects showed agreement between the two procedures in 58/68 (85.3%): both were normal in 25 cases (36.8%) and pathological in 33 (48.5%) (p < 0.001). The diagnoses established by the two techniques in CAPH subjects were concordant in 51/68 (75%). In the other 17 (25%), two had normal EUS and abnormal S-MRCP (one pancreas divisum and one SOD); eight had normal S-MRCP and abnormal EUS (eight had signs suggesting chronic pancreatitis, one associated with neuroendocrine tumor), seven had abnormal EUS and S-MRCP but with different diagnoses: two had signs suggesting chronic pancreatitis at EUS but SOD dysfunction at S-MRCP, five had IPMN at EUS but signs suggesting chronic pancreatitis at S-MRCP in three, SOD in the fourth and cysts in the fifth (Table 6). In two cases, one with neuroendocrine tumor and one with main duct IPMN, the diagnosis was confirmed by surgery. We repeated S-MRCP in patients with CP (n = 21), otherwise we followed patients with IPMN according to international guidelines (n = 9) [18,19]. All findings were confirmed at 1 year of follow up.
3.5. Laboratory findings Fecal elastase was abnormally low in three CAPH patients, all with signs consistent with chronic pancreatitis at both EUS and SMRCP. One CAPH case (1.5%) was heterozygous for the F508 gene mutation.
Table 6 EUS and S-MRCP diagnoses in the CAPH group. S-MRCP (no.)
EUS (no.) Normal PD ± CP IPMN CP NET ± CP Total
Total
Normal
PD ± CP
IPMN
CP
SOD
Cyst
25 0 0 7 1 33
1 11 0 0 0 12
0 0 5 0 0 5
0 0 3 10 0 13
1 0 1 2 0 4
0 0 1 0 0 1
27 11 10 19 1 68
CAPH: chronic asymptomatic pancreatic hyperenzymemia; PD: pancreas divisum; CP: chronic pancreatitis; IPMN: intraductal papillary mucinous neoplasia; SOD: sphincter of Oddi dysfunction; NET: neuroendocrine tumor; EUS: endoscopic ultrasound; S-MRCP: secretin-magnetic resonance cholangio-pancreatography.
4. Discussion This prospective case-control study shows that a diagnostic approach with EUS and S-MRCP for people with CAPH may detect pancreatic abnormalities in more than 60%, significantly more than shown by EUS alone in a control group matched for age and sex. The present study was only designed to assess the diagnostic approach of these two procedures in people with CAPH and not their use to follow up the pancreatic abnormalities over time. A limitation of the study was that controls were enrolled only for EUS and not SMRCP. However, the patients with submucosal lesions of the gastric fundus selected as controls were not suitable for MRCP as well. A worthwhile point is that this is the first study to systematically employ EUS in the diagnostic approach for CAPH. The results confirm those of two other series of CAPH patients in which MRCP or S-MRCP was used as the investigational procedure [6,8]. One study was by our group [6] and compared MRCP and S-MRCP in 25 consecutive patients with chronic pancreatic hyperenzymemia and 28 consecutive age-matched controls with recurrent upper abdominal pain and normal pancreatic enzymemia. S-MRCP gave a significantly higher rate of abnormal pancreatic morphological findings in patients with chronic pancreatic hyperenzymemia (52%) than controls (3.6%). The study by Mortele et al. [8], found a significantly higher rate of pancreas divisum and small cystic lesions at MRCP in 54 patients with CAPH compared to 579 controls. EUS was first evaluated in an observational prospective study [5] in about 30% of 75 patients with CAPH, as second-level imaging procedure after abdominal ultrasonography, as an alternative to or combined with computer tomography or MRCP. Like in the present study, this imaging detected pancreatic abnormalities in half the cases. EUS is usually considered the most sensitive imaging technique to identify pancreatic alterations of the ducts and the parenchyma, and S-MRCP is indicated for the entire ductal system including its dynamic changes under secretin stimulation. In persons with CAPH, EUS had the advantage over MRCP of being more sensitive for detecting signs of chronic pancreatitis, including early lesions, or small solid or fluid lesions. However, EUS has the disadvantage of being invasive and more operator-dependent. MRCP with secretin stimulation is not available in many centers and the longer duration of the procedure and costs of the hormone have to be considered. On the basis of these considerations, in the diagnostic approach to persons with CAPH, one can decide whether to use either EUS plus S-MRCP, or only one. In this study, EUS alone detected pancreatic abnormalities in 60.3% of cases, S-MRCP in 51.5%. Adding S-MRCP when EUS gave a normal result, the overall identification of pancreatic abnormalities would be only 3% better whereas when S-MRCP was normal, the detection rate with EUS added could improve by 9%. It should be pointed out that 22% of subjects in CAPH group had clinical relevant finding at imaging (1 NET, 1 Main duct type IPMN, 9 Branch type IPMN, 4 EUS findings consistent with CP) and the patients needed follow-up or surgery. However, it is important to bear in mind not only the sensitivity of the two procedures for detecting pancreatic abnormalities but also the concordance of the diagnosis. The diagnoses with EUS and S-MRCP were concordant in 75% of CAPH cases and in the remaining 25% EUS showed up abnormalities undetected by S-MRCP, or changed the diagnosis in more patients than with S-MRCP. It explains why both EUS and S-MRCP should use in the initial diagnostic assessment of CAPH subject. EUS would have missed one case of pancreas divisum and all four-suspected SOD, a diagnosis possible only with secretin stimulation. The diagnostic superiority of EUS over S-MRCP was due to its detection of more signs suggestive for chronic pancreatitis (32.3%) and IPMN (14.7%), the two most frequent diseases detected by EUS in about half the patients with CAPH. EUS identified more patients with chronic pancreatitis
Please cite this article in press as: Di Leo M, et al. Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia. Dig Liver Dis (2016), http://dx.doi.org/10.1016/j.dld.2016.08.109
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than S-MRCP. However, in a previous study the two methods together had high accuracy for chronic pancreatitis diagnosis and were complementary when used together [20]. EUS also proved more sensitive than S-MRCP for diagnosing IPMN, identifying 50% more cases. This might be because EUS can detect a communication between the cyst and the main pancreatic duct better than S-MRCP and might be more sensitive to cystic lesions smaller than 5 mm. In this study, while the diagnosis of neuroendocrine tumor and main duct-type IPMN was confirmed by surgery, that of chronic pancreatitis and branch duct IPMN had no ‘gold standard’. The criteria for diagnosing chronic pancreatitis have often been debated with the aim of achieving consensus. EUS is used as the reference procedure, but the diagnosis is considered to be most reliable only when there are more than four [21] or at least two established major or one major and two minor [14] ductal and/or parenchymal EUS criteria. In this study, four patients in the CAPH group had EUS signs consistent with chronic pancreatitis, while 18 had EUS signs suggestive of chronic pancreatitis. These cases will need to be evaluated in follow-up studies to assess whether “painless” early chronic pancreatitis progresses with time. However, if we do not consider “signs suggestive for” as a true diagnosis of chronic pancreatitis, there would be 33.8% with CAPH and abnormal EUS. Nine of the ten patients with CAPH had branch duct IPMN. At present, EUS is the best procedure for this diagnosis and, as established by international guidelines [18], a scheduled pancreatic imaging re-evaluation is needed only to assess the prognosis. The present study showed that in persons with CAPH, a normal or abnormal EUS was influenced by mean age, but not by alcohol and smoking. Those with CAPH and EUS anomalies were significantly older than those with normal EUS. This difference might be due to the higher incidence of chronic pancreatitis and IPMN in higher quartiles of age. This seems to confirm previous reports of a higher frequency of changes consistent with chronic pancreatitis and of IPMN with increasing age of patients examined by EUS [22,23]. However, it is important to note that in the present study the mean age of the control and CAPH group was not significantly different. From a pathogenic point of view, CAPH might be caused by chronic obstructive alterations [24], such as those of the pancreatic diseases in these patients. This mechanism can be assumed in patients with suspected SOD in which S-MRCP shows impaired outflow of the pancreatic juice through the pancreatic sphincter [17,25]. S-MRCP has good sensitivity for the diagnosis of SOD and assesses both juxta-papillary duct caliber and, at the same time, that of the entire pancreatic ductal system [26,27]. Even the association of CAPH and IPMN might be linked to an obstructive mechanism, in this case caused by the mucin produced by the tumor [28]. The frequency of IPMN in this study (14.7%) was higher than that reported by Pezzilli et al. [5] (6.7%) in CAPH patients. This might be explained by the systematic use of EUS in the diagnostic approach for these patients. An obstructive mechanism might also explain the association of pancreas divisum and CAPH, despite the absence of pancreatic duct dilation in patients with this enzymatic alteration [29]. Pancreas divisum was detected in 17.6% of CAPH subjects in this series, a rate similar to that reported by other authors [8,10]. Both IPMN and pancreas divisum have been counted among the obstructive etiologies of the pancreatic duct in patients with acute pancreatitis [30,31]. EUS and/or S-MRCP alterations compatible with chronic pancreatitis were detected more frequently in the CAPH patients in this study (32.4%). However, the true significance of these changes in CAPH is not clear. One hypothesis regarding the pathogenic mechanism of hyperenzymemia is the slow discharge of pancreatic juice: this might be inadequate to trigger an inflammatory process such as pancreatitis, but sufficient to induce a disorder of the normal process of pancreatic intracellular exocytosis and, therefore,
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dispersion of pancreatic enzymes in the blood across the basolateral membrane of the acinar cell, as already suggested in the literature. In conclusion, in persons with chronic asymptomatic pancreatic hyperenzymemia, alongside careful clinical evaluation and abdominal ultrasonography, the diagnostic approach with imaging techniques such as S-MRCP and EUS identifies pancreatic abnormalities in more than half the cases. We therefore recommend a diagnostic approach with these two imaging procedures for these people, with priority to EUS, before chronic asymptomatic pancreatic hyperenzymemia can be really considered a non-pathological condition, or Gullo’s syndrome. Prospective and controlled trials are needed to further clarify whether pancreatic morphological abnormalities in asymptomatic subjects with pancreatic hyperenzymemia are more frequent than in controls. Conflict of interest None declared. References [1] Gullo L. Chronic nonpathological hyperamylasemia of pancreatic origin. Gastroenterology 1996;110:1905–8. [2] Gullo L. Benign pancreatic hyperenzymemia or Gullo’s syndrome. Journal of the Pancreas 2006;7:241–2, author reply 243–4. [3] Gullo L. Familial pancreatic hyperenzymemia. Pancreas 2000;20:158–60. [4] Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clinical Gastroenterology and Hepatology 2007;5:70–4. [5] Pezzilli R, Morselli-Labate AM, Casadei R, et al. Chronic asymptomatic pancreatic hyperenzymemia is a benign condition in only half of the cases: a prospective study. Scandinavian Journal of Gastroenterology 2009;44:888–93. [6] Testoni PA, Mariani A, Curioni S, et al. Pancreatic ductal abnormalities documented by secretin-enhanced MRCP in asymptomatic subjects with chronic pancreatic hyperenzymemia. American Journal of Gastroenterology 2009;104:1780–6. [7] Gullo L, Lucrezio L, Calculli L, et al. Magnetic resonance cholangiopancreatography in asymptomatic pancreatic hyperenzymemia. Pancreas 2009;38:396–400. [8] Mortele KJ, Wiesner W, Zou KH, et al. Asymptomatic nonspecific serum hyperamylasemia and hyperlipasemia: spectrum of MRCP findings and clinical implications. Abdominal Imaging 2004;29:109–14. [9] Donati F, Boraschi P, Gigoni R, et al. Secretin-stimulated MR cholangiopancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia. European Journal of Radiology 2010;75:e38–44. [10] Amodio A, Manfredi R, Katsotourchi AM, et al. Prospective evaluation of subjects with chronic asymptomatic pancreatic hyperenzymemia. American Journal of Gastroenterology 2012;107:1089–95. [11] Mariani A. Chronic asymptomatic pancreatic hyperenzymemia: is it a benign anomaly or a disease? Journal of the Pancreas 2010;11:95–8. [12] Uomo G, Gallucci F, Madrid E, et al. Pancreatic functional impairment following acute necrotizing pancreatitis: long-term outcome of a non-surgically treated series. Digestive and Liver Disease 2010;42:149–52. [13] Naruse S, Ishiguro H, Ko SB, et al. Fecal pancreatic elastase: a reproducible marker for severe exocrine pancreatic insufficiency. Journal of Gastroenterology 2006;41:901–8. [14] Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointestinal Endoscopy 2009;69:1251–61. [15] Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756–9. [16] Schreyer AG, Jung M, Riemann JF, et al. S3 guideline for chronic pancreatitis – diagnosis, classification and therapy for the radiologist. Rofo 2014;186:1002–8. [17] Mariani A, Curioni S, Zanello A, et al. Secretin MRCP and endoscopic pancreatic manometry in the evaluation of sphincter of Oddi function: a comparative pilot study in patients with idiopathic recurrent pancreatitis. Gastrointestinal Endoscopy 2003;58:847–52. [18] Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–97. [19] Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32. [20] Pungpapong S, Wallace MB, Woodward TA, et al. Accuracy of endoscopic ultrasonography and magnetic resonance cholangiopancreatography for the diagnosis of chronic pancreatitis: a prospective comparison study. Journal of Clinical Gastroenterology 2007;41:88–93. [21] Wiersema MJ, Hawes RH, Lehman GA, et al. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993;25:555–64. [22] Petrone MC, Arcidiacono PG, Perri F, et al. Chronic pancreatitis-like changes detected by endoscopic ultrasound in subjects without signs of pancreatic
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Digestive Endoscopy
Pancreatic morpho-functional imaging as a diagnostic approach for chronic asymptomatic pancreatic hyperenzymemia Milena Di Leo a , Maria Chiara Petrone b , Raffaella Alessia Zuppardo a , Giulia Martina Cavestro a , Paolo Giorgio Arcidiacono b , Pier Alberto Testoni a , Alberto Mariani b,∗ a Gastroenterology and Gastrointestinal Endoscopy Unit, Division of Experimental Oncology, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy b Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Vita-Salute San Raffaele University, Milan, Italy
a r t i c l e
i n f o
Article history: Received 29 February 2016 Accepted 3 August 2016 Available online xxx Keywords: EUS MRCP Pancreas Secretin stimulation
a b s t r a c t Background: Magnetic resonance cholangio-pancreatography (MRCP) findings in people with chronic asymptomatic pancreatic hyperenzymemia (CAPH) have shifted the hypothesis that CAPH is always non-pathological. However, there have been no studies including both secretin-MRCP (S-MRCP) and endoscopic ultrasonography (EUS) to examine the pancreatic morphology in these subjects. Aim: To prospectively assess the diagnostic approach for CAPH using both pancreatic EUS and S-MRCP. Methods: In a case-control prospective study from January 2010 to December 2014, 68 consecutive subjects with CAPH were scheduled to undergo S-MRCP and EUS (CAPH group) in a tertiary care setting. In the same period, the EUS findings of this group were compared with 68 patients examined by EUS alone for submucosal lesions of the gastric fundus, matched for sex and age (control group). Results: EUS detected pancreatic alterations in 60.3% of the CAPH group and 13.2% of controls (p < 0.001). S-MRCP showed pancreatic alterations in 51.5% in the CAPH group. With the combined procedures, pancreatic abnormalities were detected in 63.3%. The diagnoses established by the two techniques were concordant in 51 (75%) of the 68 CAPH subjects; in the remaining 17 (25%) the two methods gave additional information. Conclusions: In people with CAPH S-MRCP and EUS are both recommended in order to detect pancreatic abnormalities before this biochemical alteration is confirmed as benign CAPH, or Gullo’s syndrome. © 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
1. Introduction Patients with no clinical symptoms occasionally present high serum concentrations of pancreatic enzymes. This condition is called “chronic asymptomatic pancreatic hyperenzymemia” [1] (CAPH) or Gullo’s syndrome [2] in honor of the first author to describe it. The syndrome is defined as chronic abnormally high plasma concentrations of pancreatic enzymes in asymptomatic patients with no evidence of pancreatic alterations. Since that first study, further characteristics have been clarified, such as a familial
∗ Corresponding author at: Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute IRCCS, Via Olgettina 60, 20132 Milano, Italy. Fax: +39 2 26433491. E-mail address: [email protected] (A. Mariani).
form [3], and wide daily fluctuations in serum concentrations [4]¸ so the condition is considered benign. However, magnetic resonance cholangio-pancreatography (MRCP) examination of these people, with or without secretin stimulation [5–10], found pancreatic abnormalities such as pancreas divisum, early chronic pancreatitis, pancreatic cysts, intraductal pancreatic mucinous neoplasia (IPMN) and pancreatic tumors, or dysfunction of the sphincter of Oddi (SOD). These studies showed that abnormalities in the pancreatic ductal system and parenchyma could be found in up to half the people investigated. A significant proportion had clinical disease. These findings led to the hypothesis that CAPH may not always be benign and pancreatic imaging is indicated to exclude an underlying disease [11]. As yet no studies systematically including S-MRCP and EUS in the diagnostic investigation of CAPH have been reported. The aim of this prospective case-control study was to assess the diagnostic approach for people with CAPH, using EUS and S-MRCP.
http://dx.doi.org/10.1016/j.dld.2016.08.109 1590-8658/© 2016 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
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2. Materials and methods 2.1. Patient enrollment In the present case-control prospective study, over a five-year period, all consecutive persons with CAPH were scheduled to undergo S-MRCP and EUS in our center, according to a standard study protocol approved by the institutional review board. EUS findings of this CAPH group were compared to those of patients who had undergone EUS investigation in the same period for submucosal lesions of the gastric fundus, matched for sex and age (control group). S-MRCP was not done in the control group. CAPH was defined as asymptomatic high concentrations of serum amylase and lipase on at least three occasions in one year, with a normal pancreas at trans-abdominal ultrasonography and/or CT scan. The study was approved by the institutional ethics committee and run in accordance with criteria for Good Clinical Practice and the World Medical Association Declaration of Helsinki. Informed consent regarding study procedures and data management for scientific purposes was routinely obtained from all patients. 2.2. Exclusion criteria CAPH subjects were excluded if at least one of the following was found: (a) no informed consent; (b) under 18 years old; (c) pancreatic pain; (d) evidence of pancreatic pathology at previous radiological evaluation; (e) neoplasia; (f) contraindication to MRCP and/or EUS; (g) HBV or HCV infection; (h) renal insufficiency; (i) celiac diseases; (j) macroamylasemia or macrolipasemia; (k) high serum cholesterol or triglycerides; (l) endocrine or exocrine pancreatic insufficiency; (m) alcohol intake more than 60 g/day; (n) hyperenzymemia for less than 12 months; (o) previous surgery and/or endoscopy of the pancreas or the papilla of Vater; (p) pregnancy; (q) past surgical procedures that could impair complete visualization of the pancreas. Exclusion criteria in the control group were: (a) no informed consent; (b) under 18 years old; (c) alcohol intake more than 60 g/day; (d) evidence of pancreatic pathology; (e) pregnancy; (f) past surgical procedures that could impair complete visualization of the pancreas. 2.3. Clinical evaluation Demographic data, body mass index (BMI), daily alcohol consumption, smoking habit, and detailed clinical history were recorded for all study participants. In addition, at enrollment, fecal elastase levels were obtained for all CAPH cases (normal value 200 g/g [12,13]) and 50 of the most frequent CFTR gene mutations in populations of European origin (Kit Elucigene® CF-EU2v1, Delta Diagnostics, UK) were examined. 2.4. EUS EUS procedures were done by one experienced endosonographer (MCP, with more than 1000 EUS per year in the last five years). A linear-scanning echoendoscope (EG-3830UT, EG-3630U, FG36UX; Pentax, Hamburg, Germany) at 5–10 MHz was used. During procedures patients were deeply sedated with propofol (Diprivan® , AstraZeneca, Italy) infused with a TCI pump (Terufusion-TIVA/TCI TE372 Terumo Europe N.V., Leuven, Belgium) using the Marsh TCI model (DiprifusorTM AstraZeneca, Macclesfield, UK), under an anesthetist’s supervision. After completion of the examination for submucosal gastric lesions, the endosonographer carefully scanned the pancreas, looking at the head and tail from the proximal stomach and, after that, the body and the uncinate process from the duodenum. The EUS
diagnosis of chronic pancreatitis was based on Rosemont criteria [14]. In the CAPH group, EUS operator was blind respect to S-MRCP findings but it knew the disease of patient at the time of procedure. 2.5. MR cholangio-pancreatography with secretin MRCP was carried out using a 1.5 T magnet (Signa horizon; GE Medical Systems, Milwaukee, WI) and phased-array coils. Single-shot fast-spin echo, breath-hold, 2D, heavily T2-weighted images were employed. The following parameters were applied: ∞/800–1400; thickness 40–50 mm; matrix 256–512; field of view 35–40 cm; acquisition time 2 s. Patients took 200 mL of negative super-paramagnetic oral contrast agent (Lumirem; Guerbet, Aulnay-sous-Bois, France) before the imaging procedure. All patients examined by MRCP received an i.v. bolus injection of secretin (Secrelux; Goldham, Zusmarshausen, Germany; 1 IU/kg) to enhance the pancreatic ductal morphology. Ductal findings were evaluated according to the Cambridge classification and chronic pancreatitis was diagnosed and graded on the basis of the different abnormal ductal findings [15,16]. SOD was diagnosed if the main pancreatic duct diameter at the body 15 min after secretin stimulation was ≥1 mm larger than the basal value [17]. Although the outcome of CAPH is not an endpoint of the present study, we scheduled a follow-up in all CAPH subjects with abnormal findings at EUS or S-MRCP. 2.6. Statistical analysis Mean and standard deviation (SD) were used for continuous variables, percentages for categorical variables. Groups were compared using the Mann–Whitney test for continuous variables (on account of their non-normal distribution) and Yates corrected chi square test or Fisher’s test for categorical variables. Significance was set at p < 0.05 with two tails. Data were analyzed using the SPSS 21.0 system software (Chicago, IL, USA). 3. Results 3.1. Study population We enrolled 68 CAPH subjects and 68 controls from January 2010 to December 2014. Nine CAPH patients were excluded, three because of hepatic disease, two for celiac disease, one for renal insufficiency, two for contraindication to EUS and one to SMRCP. The two groups were homogeneous for all variables except cigarette smoking (Table 1). 3.2. EUS EUS pancreatic alterations were significantly more frequent in the CAPH than control group (60.3% and 13.2%; p < 0.001) (Table 2). This difference was mainly due to the higher frequency of signs of chronic pancreatitis in the CAPH group (32.4%) than in controls (4.4%) (p < 0.001). According to the Rosemont classification, there were significantly more people with EUS signs “suggestive of” and “consistent with” chronic pancreatitis in the CAPH group (Table 3). The persons with normal and abnormal EUS in the CAPH group were similar for both smoking and alcohol consumption, time elapsed from the first detection of pancreatic hyperenzymemia and EUS investigation, and serum lipase and amylase levels. CAPH subjects with normal EUS findings were significantly younger than those with abnormal EUS (Table 4). Among the EUS abnormalities in the CAPH group, the frequency of chronic pancreatitis and IPMN rose with quartiles of age more than in people with normal EUS (p = 0.02).
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Table 1 Main demographic data and characteristics of study population.
Males [no. (%)] Age [mean (SD)] BMI [mean (SD)] Cigarette smoking Never [no. (%)] Previous [no. (%)] Active [no. (%)] Pack-years [mean (SD)] Alcohol consumption Never [no. (%)] Previous [no. (%)] Active [no. (%)] Alcohol/day [mean (SD)] g Duration of alcohol use [mean (SD)] yrs
Control group (n = 68)
CAPH group (n = 68)
37 (54.4%) 59.1 (14.4) 24.6 (3.5)
37 (54.4%) 57.1 (15.4) 23.7 (3.5)
p 1.000 0.466 0.215
38 (55.9) 3 (4.4) 27 (39.7) 17.4 (20.9)
51 (75.0) 11 (16.2) 6 (8.8) 7.8 (16.2)
<0.001
51 (75.0) 3 (4.4) 14 (20.6) 3.1 (6.2) 10.6 (20.1)
49 (72.1) 6 (8.8) 13 (19.1) 6.0 (15.2) 9.4 (16.9)
0.584
0.010
0.461 0.978
CAPH: chronic asymptomatic pancreatic hyperenzymemia; BMI: body mass index.
Table 2 EUS findings in the two groups.
Normal [no. (%)] Abnormalities [no. (%)] Pancreas divisum [no. (%)] IPMN [no. (%)] Main duct type [no. (%)] Branch type [no. (%)] Chronic pancreatitis [no. (%)] Pancreas divisum and chronic pancreatitis [no. (%)] NET and chronic pancreatitis [no. (%)]
Control group (n = 68)
CAPH group (n = 68)
p
59 (86.8) 9 (13.2) 1 (1.5) 5 (7.4) 0 5 3 (4.4) 0 0
27 (39.7) 41 (60.3) 9 (13.2) 10 (14.7) 1 9 19 (27.9) 2 (2.9) 1 (1.5)
< 0.001
<0.001
CAPH: chronic asymptomatic pancreatic hyperenzymemia; IPMN: intraductal papillary mucinous neoplasia; NET: neuroendocrine tumor.
Table 3 EUS diagnosis of chronic pancreatitis (CP) according to the Rosemont classification.
No CP [no. (%)] Other abnormality [no. (%)] Normal [no. (%)] Indeterminate for CP [no. (%)] CP [no. (%)] Suggestive of CP [no. (%)] Consistent with CP [no. (%)]
Control group (n = 68)
CAPH group (n = 68)
p
65 (95.6) 6 (8.8) 54 (79.4) 5 (7.4) 3 (4.4) 1 (1.5) 2 (2.9)
46 (67.6) 19 (27.9) 24 (35.3) 3 (4.4) 22 (32.4) 18 (26.5) 4 (5.9)
< 0.001
CAPH: chronic asymptomatic pancreatic hyperenzymemia; CP: chronic pancreatitis.
Table 4 Main demographic data of subjects in the CAPH group with normal or abnormal EUS.
Males [no. (%)] Age [mean (SD)] yrs BMI [mean (SD)] Cigarette smoking Never [no. (%)] Previous [no. (%)] Active [no. (%)] Pack-years [mean (SD)] Alcohol consumption Never [no. (%)] Previous [no. (%)] Active [no. (%)] Alcohol/day [mean (SD)] g Duration of alcohol use [mean (SD)] yrs Time from first detection of hyperenzymemia and EUS [mean (SD)] yrs Amylase × u.n.l.a (max) [mean (SD)] Lipase × u.n.l.a (max) [mean (SD)]
Normal EUS (n = 27)
Abnormal EUS (n = 41)
p
11 (40.7) 50.6 (16.8) 22.9 (3.8)
26 (63.4) 61.4 (12.8) 24.2 (3.2)
0.084 0.007 0.130
22 (81.5) 3 (11.1) 2 (7.4) 3.4 (9.4)
29 (70.7) 8 (19.5) 4 (7.4) 10.7 (19.1)
0.588
20 (74.1) 2 (7.4) 5 (18.5) 6.0 (18.3) 7.9 (15.8) 2.6 (1.8) 3.1 (1.8) 4.1 (2.3)
29 (70.7) 4 (9.8) 8 (19.5) 6.0 (13.0) 10.4 (17.8) 2.4 (2.3) 3.8 (5.3) 4.3 (4.8)
0.935
0.130
0.743 0.680 0.193 0.220 0.485
CAPH: chronic asymptomatic pancreatic hyperenzymemia; BMI: body mass index; EUS: endoscopic ultrasonography. a Number of times the upper normal limit (u.n.l.).
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Table 5 S-MRCP (secretin-magnetic resonance cholangio-pancreatography) findings in 68 persons with CAPH.
Normal Abnormal Pancreas divisum IPMN Chronic pancreatitis SOD Cyst Pancreas divisum and chronic pancreatitis
Number
%
33 35 11 5 13 4 1 1
48.5 51.5 16.2 7.4 19.1 5.9 1.5 1.5
CAPH: chronic asymptomatic pancreatic hyperenzymemia; IPMN: intraductal papillary mucinous neoplasia; SOD: sphincter of Oddi dysfunction.
3.3. S-MRCP S-MRCP detected pancreatic abnormalities in 35 people in the CAPH group (51.5%) (Table 5).
3.4. Comparison of EUS and S-MRCP findings The comparison of normal and abnormal EUS and S-MRCP findings in CAPH subjects showed agreement between the two procedures in 58/68 (85.3%): both were normal in 25 cases (36.8%) and pathological in 33 (48.5%) (p < 0.001). The diagnoses established by the two techniques in CAPH subjects were concordant in 51/68 (75%). In the other 17 (25%), two had normal EUS and abnormal S-MRCP (one pancreas divisum and one SOD); eight had normal S-MRCP and abnormal EUS (eight had signs suggesting chronic pancreatitis, one associated with neuroendocrine tumor), seven had abnormal EUS and S-MRCP but with different diagnoses: two had signs suggesting chronic pancreatitis at EUS but SOD dysfunction at S-MRCP, five had IPMN at EUS but signs suggesting chronic pancreatitis at S-MRCP in three, SOD in the fourth and cysts in the fifth (Table 6). In two cases, one with neuroendocrine tumor and one with main duct IPMN, the diagnosis was confirmed by surgery. We repeated S-MRCP in patients with CP (n = 21), otherwise we followed patients with IPMN according to international guidelines (n = 9) [18,19]. All findings were confirmed at 1 year of follow up.
3.5. Laboratory findings Fecal elastase was abnormally low in three CAPH patients, all with signs consistent with chronic pancreatitis at both EUS and SMRCP. One CAPH case (1.5%) was heterozygous for the F508 gene mutation.
Table 6 EUS and S-MRCP diagnoses in the CAPH group. S-MRCP (no.)
EUS (no.) Normal PD ± CP IPMN CP NET ± CP Total
Total
Normal
PD ± CP
IPMN
CP
SOD
Cyst
25 0 0 7 1 33
1 11 0 0 0 12
0 0 5 0 0 5
0 0 3 10 0 13
1 0 1 2 0 4
0 0 1 0 0 1
27 11 10 19 1 68
CAPH: chronic asymptomatic pancreatic hyperenzymemia; PD: pancreas divisum; CP: chronic pancreatitis; IPMN: intraductal papillary mucinous neoplasia; SOD: sphincter of Oddi dysfunction; NET: neuroendocrine tumor; EUS: endoscopic ultrasound; S-MRCP: secretin-magnetic resonance cholangio-pancreatography.
4. Discussion This prospective case-control study shows that a diagnostic approach with EUS and S-MRCP for people with CAPH may detect pancreatic abnormalities in more than 60%, significantly more than shown by EUS alone in a control group matched for age and sex. The present study was only designed to assess the diagnostic approach of these two procedures in people with CAPH and not their use to follow up the pancreatic abnormalities over time. A limitation of the study was that controls were enrolled only for EUS and not SMRCP. However, the patients with submucosal lesions of the gastric fundus selected as controls were not suitable for MRCP as well. A worthwhile point is that this is the first study to systematically employ EUS in the diagnostic approach for CAPH. The results confirm those of two other series of CAPH patients in which MRCP or S-MRCP was used as the investigational procedure [6,8]. One study was by our group [6] and compared MRCP and S-MRCP in 25 consecutive patients with chronic pancreatic hyperenzymemia and 28 consecutive age-matched controls with recurrent upper abdominal pain and normal pancreatic enzymemia. S-MRCP gave a significantly higher rate of abnormal pancreatic morphological findings in patients with chronic pancreatic hyperenzymemia (52%) than controls (3.6%). The study by Mortele et al. [8], found a significantly higher rate of pancreas divisum and small cystic lesions at MRCP in 54 patients with CAPH compared to 579 controls. EUS was first evaluated in an observational prospective study [5] in about 30% of 75 patients with CAPH, as second-level imaging procedure after abdominal ultrasonography, as an alternative to or combined with computer tomography or MRCP. Like in the present study, this imaging detected pancreatic abnormalities in half the cases. EUS is usually considered the most sensitive imaging technique to identify pancreatic alterations of the ducts and the parenchyma, and S-MRCP is indicated for the entire ductal system including its dynamic changes under secretin stimulation. In persons with CAPH, EUS had the advantage over MRCP of being more sensitive for detecting signs of chronic pancreatitis, including early lesions, or small solid or fluid lesions. However, EUS has the disadvantage of being invasive and more operator-dependent. MRCP with secretin stimulation is not available in many centers and the longer duration of the procedure and costs of the hormone have to be considered. On the basis of these considerations, in the diagnostic approach to persons with CAPH, one can decide whether to use either EUS plus S-MRCP, or only one. In this study, EUS alone detected pancreatic abnormalities in 60.3% of cases, S-MRCP in 51.5%. Adding S-MRCP when EUS gave a normal result, the overall identification of pancreatic abnormalities would be only 3% better whereas when S-MRCP was normal, the detection rate with EUS added could improve by 9%. It should be pointed out that 22% of subjects in CAPH group had clinical relevant finding at imaging (1 NET, 1 Main duct type IPMN, 9 Branch type IPMN, 4 EUS findings consistent with CP) and the patients needed follow-up or surgery. However, it is important to bear in mind not only the sensitivity of the two procedures for detecting pancreatic abnormalities but also the concordance of the diagnosis. The diagnoses with EUS and S-MRCP were concordant in 75% of CAPH cases and in the remaining 25% EUS showed up abnormalities undetected by S-MRCP, or changed the diagnosis in more patients than with S-MRCP. It explains why both EUS and S-MRCP should use in the initial diagnostic assessment of CAPH subject. EUS would have missed one case of pancreas divisum and all four-suspected SOD, a diagnosis possible only with secretin stimulation. The diagnostic superiority of EUS over S-MRCP was due to its detection of more signs suggestive for chronic pancreatitis (32.3%) and IPMN (14.7%), the two most frequent diseases detected by EUS in about half the patients with CAPH. EUS identified more patients with chronic pancreatitis
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than S-MRCP. However, in a previous study the two methods together had high accuracy for chronic pancreatitis diagnosis and were complementary when used together [20]. EUS also proved more sensitive than S-MRCP for diagnosing IPMN, identifying 50% more cases. This might be because EUS can detect a communication between the cyst and the main pancreatic duct better than S-MRCP and might be more sensitive to cystic lesions smaller than 5 mm. In this study, while the diagnosis of neuroendocrine tumor and main duct-type IPMN was confirmed by surgery, that of chronic pancreatitis and branch duct IPMN had no ‘gold standard’. The criteria for diagnosing chronic pancreatitis have often been debated with the aim of achieving consensus. EUS is used as the reference procedure, but the diagnosis is considered to be most reliable only when there are more than four [21] or at least two established major or one major and two minor [14] ductal and/or parenchymal EUS criteria. In this study, four patients in the CAPH group had EUS signs consistent with chronic pancreatitis, while 18 had EUS signs suggestive of chronic pancreatitis. These cases will need to be evaluated in follow-up studies to assess whether “painless” early chronic pancreatitis progresses with time. However, if we do not consider “signs suggestive for” as a true diagnosis of chronic pancreatitis, there would be 33.8% with CAPH and abnormal EUS. Nine of the ten patients with CAPH had branch duct IPMN. At present, EUS is the best procedure for this diagnosis and, as established by international guidelines [18], a scheduled pancreatic imaging re-evaluation is needed only to assess the prognosis. The present study showed that in persons with CAPH, a normal or abnormal EUS was influenced by mean age, but not by alcohol and smoking. Those with CAPH and EUS anomalies were significantly older than those with normal EUS. This difference might be due to the higher incidence of chronic pancreatitis and IPMN in higher quartiles of age. This seems to confirm previous reports of a higher frequency of changes consistent with chronic pancreatitis and of IPMN with increasing age of patients examined by EUS [22,23]. However, it is important to note that in the present study the mean age of the control and CAPH group was not significantly different. From a pathogenic point of view, CAPH might be caused by chronic obstructive alterations [24], such as those of the pancreatic diseases in these patients. This mechanism can be assumed in patients with suspected SOD in which S-MRCP shows impaired outflow of the pancreatic juice through the pancreatic sphincter [17,25]. S-MRCP has good sensitivity for the diagnosis of SOD and assesses both juxta-papillary duct caliber and, at the same time, that of the entire pancreatic ductal system [26,27]. Even the association of CAPH and IPMN might be linked to an obstructive mechanism, in this case caused by the mucin produced by the tumor [28]. The frequency of IPMN in this study (14.7%) was higher than that reported by Pezzilli et al. [5] (6.7%) in CAPH patients. This might be explained by the systematic use of EUS in the diagnostic approach for these patients. An obstructive mechanism might also explain the association of pancreas divisum and CAPH, despite the absence of pancreatic duct dilation in patients with this enzymatic alteration [29]. Pancreas divisum was detected in 17.6% of CAPH subjects in this series, a rate similar to that reported by other authors [8,10]. Both IPMN and pancreas divisum have been counted among the obstructive etiologies of the pancreatic duct in patients with acute pancreatitis [30,31]. EUS and/or S-MRCP alterations compatible with chronic pancreatitis were detected more frequently in the CAPH patients in this study (32.4%). However, the true significance of these changes in CAPH is not clear. One hypothesis regarding the pathogenic mechanism of hyperenzymemia is the slow discharge of pancreatic juice: this might be inadequate to trigger an inflammatory process such as pancreatitis, but sufficient to induce a disorder of the normal process of pancreatic intracellular exocytosis and, therefore,
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dispersion of pancreatic enzymes in the blood across the basolateral membrane of the acinar cell, as already suggested in the literature. In conclusion, in persons with chronic asymptomatic pancreatic hyperenzymemia, alongside careful clinical evaluation and abdominal ultrasonography, the diagnostic approach with imaging techniques such as S-MRCP and EUS identifies pancreatic abnormalities in more than half the cases. We therefore recommend a diagnostic approach with these two imaging procedures for these people, with priority to EUS, before chronic asymptomatic pancreatic hyperenzymemia can be really considered a non-pathological condition, or Gullo’s syndrome. Prospective and controlled trials are needed to further clarify whether pancreatic morphological abnormalities in asymptomatic subjects with pancreatic hyperenzymemia are more frequent than in controls. Conflict of interest None declared. References [1] Gullo L. Chronic nonpathological hyperamylasemia of pancreatic origin. Gastroenterology 1996;110:1905–8. [2] Gullo L. Benign pancreatic hyperenzymemia or Gullo’s syndrome. Journal of the Pancreas 2006;7:241–2, author reply 243–4. [3] Gullo L. Familial pancreatic hyperenzymemia. Pancreas 2000;20:158–60. [4] Gullo L. Day-to-day variations of serum pancreatic enzymes in benign pancreatic hyperenzymemia. Clinical Gastroenterology and Hepatology 2007;5:70–4. [5] Pezzilli R, Morselli-Labate AM, Casadei R, et al. Chronic asymptomatic pancreatic hyperenzymemia is a benign condition in only half of the cases: a prospective study. Scandinavian Journal of Gastroenterology 2009;44:888–93. [6] Testoni PA, Mariani A, Curioni S, et al. Pancreatic ductal abnormalities documented by secretin-enhanced MRCP in asymptomatic subjects with chronic pancreatic hyperenzymemia. American Journal of Gastroenterology 2009;104:1780–6. [7] Gullo L, Lucrezio L, Calculli L, et al. Magnetic resonance cholangiopancreatography in asymptomatic pancreatic hyperenzymemia. Pancreas 2009;38:396–400. [8] Mortele KJ, Wiesner W, Zou KH, et al. Asymptomatic nonspecific serum hyperamylasemia and hyperlipasemia: spectrum of MRCP findings and clinical implications. Abdominal Imaging 2004;29:109–14. [9] Donati F, Boraschi P, Gigoni R, et al. Secretin-stimulated MR cholangiopancreatography in the evaluation of asymptomatic patients with non-specific pancreatic hyperenzymemia. European Journal of Radiology 2010;75:e38–44. [10] Amodio A, Manfredi R, Katsotourchi AM, et al. Prospective evaluation of subjects with chronic asymptomatic pancreatic hyperenzymemia. American Journal of Gastroenterology 2012;107:1089–95. [11] Mariani A. Chronic asymptomatic pancreatic hyperenzymemia: is it a benign anomaly or a disease? Journal of the Pancreas 2010;11:95–8. [12] Uomo G, Gallucci F, Madrid E, et al. Pancreatic functional impairment following acute necrotizing pancreatitis: long-term outcome of a non-surgically treated series. Digestive and Liver Disease 2010;42:149–52. [13] Naruse S, Ishiguro H, Ko SB, et al. Fecal pancreatic elastase: a reproducible marker for severe exocrine pancreatic insufficiency. Journal of Gastroenterology 2006;41:901–8. [14] Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointestinal Endoscopy 2009;69:1251–61. [15] Sarner M, Cotton PB. Classification of pancreatitis. Gut 1984;25:756–9. [16] Schreyer AG, Jung M, Riemann JF, et al. S3 guideline for chronic pancreatitis – diagnosis, classification and therapy for the radiologist. Rofo 2014;186:1002–8. [17] Mariani A, Curioni S, Zanello A, et al. Secretin MRCP and endoscopic pancreatic manometry in the evaluation of sphincter of Oddi function: a comparative pilot study in patients with idiopathic recurrent pancreatitis. Gastrointestinal Endoscopy 2003;58:847–52. [18] Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–97. [19] Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:17–32. [20] Pungpapong S, Wallace MB, Woodward TA, et al. Accuracy of endoscopic ultrasonography and magnetic resonance cholangiopancreatography for the diagnosis of chronic pancreatitis: a prospective comparison study. Journal of Clinical Gastroenterology 2007;41:88–93. [21] Wiersema MJ, Hawes RH, Lehman GA, et al. Prospective evaluation of endoscopic ultrasonography and endoscopic retrograde cholangiopancreatography in patients with chronic abdominal pain of suspected pancreatic origin. Endoscopy 1993;25:555–64. [22] Petrone MC, Arcidiacono PG, Perri F, et al. Chronic pancreatitis-like changes detected by endoscopic ultrasound in subjects without signs of pancreatic
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