Gastrointestinal Imaging Original Research

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1 Gastrointestinal Imaging Original Research Downloaded from by on 4/21/18 from IP address Copyright ARRS. For personal use only; all rights reserved Torigoe et al. MRCP of Age-Related Change in Pancreatic Juice Flow Gastrointestinal Imaging Original Research Teruyuki Torigoe 1 Katsuyoshi Ito Akira Yamamoto Akihiko Kanki Kazuya Yasokawa Tsutomu Tamada Koji Yoshida Torigoe T, Ito K, Yamamoto A, et al. Keywords: aging, MRCP, pancreatic duct, pancreatic juice, secretory flow DOI:1.2214/AJR Received March 4, 213; accepted after revision June 6, All authors: Department of Diagnostic Radiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama , Japan. Address correspondence to K. Ito AJR 214; 22: X/14/ American Roentgen Ray Society Age-Related Change of the Secretory Flow of Pancreatic Juice in the Main Pancreatic Duct: Evaluation With Cine-Dynamic MRCP Using Spatially Selective Inversion Recovery Pulse OBJECTIVE. The purpose of this study is to evaluate age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct noninvasively by means of nonpharmacologic cine-dynamic MRCP using spatially selective inversion recovery (IR) pulse. MATERIALS AND METHODS. Fifty-three subjects without a history of pancreatic disease were included. Four-second breath-hold MRCP using spatially selective IR pulse was performed every 15 seconds during 5 minutes (acquiring a total of 2 images) in cinedynamic fashion. The secretion grade was classified into five grades by the distance of pancreatic juice inflow within the tagged area. The mean secretion grade and the frequency of secretion in cine-dynamic MRCP were compared among three age-range groups (group 1, < 4 years; group 2, 4 7 years; and group 3, > 7 years). Statistical analysis was performed using Spearman rank correlation coefficient and Kruskal-Wallis and Mann-Whitney U tests. RESULTS. The secretion grade and the frequency of secretion were significantly reduced with aging (r =.77, p <.1; and r =.74, p <.1, respectively). The mean secretion grade and the frequency of secretion were significantly lower in group 3 than in group 2 (mean grade,.36 vs 1.48, p =.1; and 4.8 vs 11.9 times, p =.1) and were lower in group 2 than in group 1 (mean grade, 1.48 vs 2.48, p <.1; and 11.9 vs 16.2 times, p =.11). CONCLUSION. Cine-dynamic MRCP using spatially selective IR pulse was able to show the age-related decrease of the secretory flow of pancreatic juice in the main pancreatic duct visually and noninvasively. T he age-related morphologic and functional changes in the pancreas have been reported in several studies [1 3]. Anatomic and histologic studies have shown that the weight of the pancreas decreases during the 7th decade of life; postmortem examinations have shown that the pancreas becomes harder and more atrophic with age; and ductal ectasia and intralobular fibrosis are histologically observed, indicating an involution of the pancreatic gland with age [4 6]. Some clinical studies investigated the relationship between aging and exocrine pancreatic secretion by using invasive tube examinations such as the secretin-cerulein test and provided the evidence for a reduced basal secretion of the pancreas during aging [7 1]. Ishibashi [11] also clarified that the volume of exocrine pancreatic secretion was significantly reduced in the elderly by means of endoscopic retrograde aspiration of pure pancreatic juice. Compared with these invasive procedures, an alternative approach to evalu- ate exocrine pancreatic secretion by secretinstimulated MRCP has been proposed [12 15]. With this technique, exocrine pancreatic secretion was estimated on the basis of the caliber change of main pancreatic duct and the increase in the amount of fluid in the small bowel before and after secretin administration [16 19]. However, this technique yielded nonphysiologic information because of the exogenous administration of secretin. Recently, it has been shown that the physiologic flow of pancreatic juice can be directly and noninvasively visualized with nonpharmacologic cine-dynamic MRCP using spatially selective inversion recovery (IR) pulse [2]. With this technique, the frequency of pancreatic juice inflow and the distance of moving pancreatic juice in the main pancreatic duct can be elucidated during a dynamic MRCP series. The purpose of the present study was to evaluate age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct noninvasively by means of cine-dynamic MRCP using spatially selective IR pulse. 122 AJR:22, May 214

2 MRCP of Age-Related Change in Pancreatic Juice Flow Downloaded from by on 4/21/18 from IP address Copyright ARRS. For personal use only; all rights reserved Materials and Methods Study Population This retrospective study was approved by our institutional review board, and informed consent for the patients was waived. In the medical records from our institution between December 21 and March 211, we searched for patients without pancreatic diseases who underwent cine-dynamic MRCP using spatially selective IR pulse as a part of pancreaticobiliary MRI examination and identified 53 consecutive patients who satisfied the inclusion criteria for this study (31 men, 22 women; mean age, 53.5 years; age range, years). Patients with a history or symptoms suggestive of pancreatic diseases were excluded. Patients with diabetes mellitus or a history of alcoholism were also excluded because these diseases affect normal pancreatic function. Reasons for patient referral for MRI included further evaluation of hepatobiliary abnormalities detected by sonography or CT (n = 22 [common bile duct stone, n = 9; gallstone, n = 8; intrahepatic bile duct dilatation, n = 1; cholangitis, n = 1; benign biliary stricture, n = 1; gallbladder lesion, n = 1; cholecystitis, n = 1]) and screening for abdominal diseases suspected by elevated serum alkaline phosphatase or γ-glutamyl transpeptidase level (n = 31). In nine patients with common bile duct stone, no patient had the impacted stone in the ampulla. Elevated serum bilirubin levels were not noted in any patients. Subjects were required to fast for at least 5 hours before the MRI examination. Patients were divided into three groups according to age as follows: group 1, less than 4 years (n = 14); group 2, 4 7 years (n = 26); and group 3, more than 7 years (n = 13). MRI Technique MRI was performed with a 1.5-T system (Excelart Vantage powered by Atlas, Toshiba Medical Systems), equipped with quadrature-detected A Fig year-old man. A, Breath-hold, thick-slab 2D MRCP without spatially selective inversion recovery pulse obtained as reference image shows normal pancreatic duct as high signal intensity. B, Placement is shown of spatially selective inversion recovery pulse with 2-mm width (parallel white lines) on head of pancreas perpendicular to main pancreatic duct. phased-array coils (16 channels with 32 elements). At the beginning of MRI examination, a package of 25 ml of negative contrast agents including 36 mg of manganese chloride tetrahydrate (Bothdel Oral Solution 1, Kyowa Hakko Kirin) was taken orally to reduce the signal from the bowel. As a part of pancreaticobiliary MRI examination, cine-dynamic MRCP with spatially selective IR pulse was performed during a respiratory suspension using a technique that has been previously described [2]. First, a breath-hold, thick-slab 2D MRCP image was obtained to depict the main pancreatic duct in the oblique-coronal plane as a reference image (Fig. 1A). The following imaging parameters were used: TR/TE, 4/5; echo train spacing, 6.5 ms; slice thickness, 5 mm; matrix, 32 32; FOV, cm; bandwidth, 488 Hz; and one acquisition. Next, a location to apply a spatially selective IR pulse (inversion time, 22 ms) with 2-mm width to null the static pancreatic juice signal was determined with this reference image. A spatially selective IR pulse was placed on the head of the pancreas perpendicular to the main pancreatic duct (Fig. 1B). Then, a breath-hold, thick-slab 2D MRCP image using the same imaging parameters was obtained in a combination with a spatially selective IR pulse. Imaging time including inversion time was 4 seconds. Breath-hold, thick-slab 2D MRCP with a spatially selective IR pulse was repeatedly performed every 15 seconds (4 seconds scan, plus 11 seconds rest for breathing, as well as for recovery of longitudinal magnetization) during 5 minutes to acquire a series of single-shot images (a total of 2 images), and a series of MRCP images were shown in cine-dynamic fashion (i.e., cine-dynamic MRCP). All patients were instructed to start breath-holding at the end of expiration when scanning. With B this method, the static pancreatic juice in the areas applied with a spatially selective IR pulse is shown as dark whereas the inflow pancreatic juice in these areas is observed as high signal when the pancreatic juice runs through the main pancreatic duct from the tail side to the head side [2]. Image Analysis All examinations were reviewed retrospectively and independently by two radiologists (with 14 and 4 years clinical experience in abdominal MRI) who had no prior knowledge of sex, age, and any clinical information of the patients on a PACS workstation (RapideyeCore, Toshiba Medical Systems). Any interpretation discrepancies were resolved by consensus with the participation of a third radiologist with 22 years experience in liver MRI. The images were presented to the readers in a random order. MR images were evaluated to determine the frequency of secretion of the pancreatic juice and the secretion grade of the pancreatic juice. Frequency of secretion was defined as the frequency of detection of inflow high signal of the pancreatic juice in the area with a spatially selective IR pulse (i.e., the frequency with which the pancreatic juice flowed into the pancreatic duct). Secretion grade was determined on the basis of the distance that the pancreatic juice moved within the pancreatic duct in the area with a spatially selective IR pulse (grade, no flow; grade 1, < 5 mm; grade 2, 5 1 mm; grade 3, mm; grade 4, > 15 mm) (Fig. 2). The mean secretion grade was defined as follows: (total of grade number) / 2. Association of age with the frequency of secretion as well as with the secretion grade was evaluated. Then, the mean secretion grade and the frequency of secretion in cine-dynamic MRCP were compared among three age-range groups to assess the age-related differences in the secretory flow of the pancreatic juice in the main pancreatic duct. Statistical analysis was performed using SPSS for Windows, version 19. (SPSS). Spearman rank correlation coefficient analysis was performed to determine the relationship of age with the frequency of secretion as well as with the secretion grade. Kruskal-Wallis and Mann-Whitney U tests were performed for comparison among the three groups. A p value less than.5 was considered to indicate a statistically significant difference. Results The pancreatic juice inflow was observed at least one time at cine-dynamic MRCP with spatially selective IR pulse in 52 (98%) of 53 patients. The mean [± SD] frequency of pancreatic juice inflow (secretion) in 53 patients was 11.3 ± 6.2 times (range, 19 times) in a series of 2 images. The mean se- AJR:22, May

3 Torigoe et al. Downloaded from by on 4/21/18 from IP address Copyright ARRS. For personal use only; all rights reserved cretion grade in 53 patients was 1.47 ± 1.1 (range, 3.4). With regard to the relationships of age with secretion grade and with frequency, the frequency of secretion was significantly reduced with aging (r =.74, p <.1) (Fig. 3). Additionally, the secretion grade also showed a significant decline with aging (r =.77, p <.1) (Fig. 4). In the comparison among the three age-range groups, the mean frequency of secretion was A D Fig. 2 Secretion grade of pancreatic juice in cine-dynamic MRCP with spatially selective inversion recovery (IR) pulse. Spatially selective IR pulse with 2-mm width was placed on area between parallel white lines (tagged area). Note scale is divided into four regions for secretion grade. Arrow denotes signal (or lack of flow signal for grade ) within tagged area. A, Secretion grade (no flow signal in tagged area). B, Secretion grade 1 (slightly high signal within < 5 mm in tagged area). C, Secretion grade 2 (high signal within 5 1 mm in tagged area). D, Secretion grade 3 (high signal within mm in tagged area). E, Secretion grade 4 (high signal > 15 mm in tagged area). significantly lower in group 3 than in group 2 (4.8 [range, 14] vs 11.9 [range, 19] times, p =.1) and was lower in group 2 than in group 1 (11.9 [range, 19] vs 16.2 [range, 11 19] times, p =.11) (Table 1), indicating that the pancreatic juice flow was more frequently observed in younger subjects than in older subjects. In addition, the mean secretion grade was significantly lower in group 3 than in group 2 (mean grade,.36 TABLE 1: Comparison of Mean Frequency of Pancreatic Juice Secretion Observed and Mean Secretion Grade Among Three Age-Range Groups Parameter Group 1 (n = 14) Group 2 (n = 26) Group 3 (n = 13) p a Age range (y) < > 7 Mean frequency of pancreatic 16.2 ± 3. b 11.9 ± 5.7 c 4.8 ± 4.1 <.1 juice secretion observed Mean secretion grade 2.48 ±.7 d 1.48 ± 1. c.36 ±.4 <.1 Note Except as otherwise indicated, data are given as mean ± SD. Frequency of secretion was defined as the frequency of detection of inflow high signal of the pancreatic juice in the area with a spatially selective inversion recovery pulse (i.e., the frequency with which the pancreatic juice flowed into the pancreatic duct). Secretion grade was determined on the basis of the distance that the pancreatic juice moved within the pancreatic duct in the area with a spatially selective inversion recovery pulse (grade, no flow; grade 1, < 5 mm; grade 2, 5 1 mm; grade 3, mm; grade 4, > 15 mm). a Difference in three groups. b Significantly different from group 2 (p =.11) and from group 3 (p <.1). c Significantly different from group 3 (p =.1). d Significantly different from group 2 (p =.3) and from group 3 (p <.1). B E [range, 1.55] vs 1.48 [range, ], p =.1) and was lower in group 2 than in group 1 (mean grade, 1.48 [range, ] vs 2.48 [range, ], p <.1) (Table 1), indicating that the distance that the pancreatic juice moved in the pancreatic duct was significantly longer in younger subjects than in older subjects. In group 1, grade 4 was assigned in 13 of 14 patients. In seven of these 14 patients, grade 4 was assigned more than 1 times in a series of 2 images. By contrast, in group 3, grade 4 was assigned in only one of 13 patients. Discussion In this study, the secretion grade and the frequency of secretion of pancreatic juice in nonpharmacologic cine-dynamic MRCP using spatially selective IR pulse were significantly reduced with aging, suggesting a decrease in exocrine pancreatic secretion. Additionally, significant differences were observed in the mean secretion grade and the frequency of secretion among three age-range groups. Some previous studies have reported that exocrine pancreatic secretion decreased with age, using measurement of fecal chymotrypsin or duodenal suction test after hormonal stimulation [7 C 124 AJR:22, May 214

4 MRCP of Age-Related Change in Pancreatic Juice Flow Downloaded from by on 4/21/18 from IP address Copyright ARRS. For personal use only; all rights reserved Frequency of Secretion Secretion Grade , 11, 21]. Their results are in agreement with our current observation. Therefore, cine-dynamic MRCP using spatially selective IR pulse has the potential to show age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct. Several factors may cause the reduction in secretion grade and frequency that implies decreased pancreatic juice secretion in older patients. First, this reduction may be associated with histologic changes observed in the elderly, such as fibrosis around the ducts Age (y) Fig. 3 Graph shows relationship between age and frequency of secretion, defined as the frequency of detection of inflow high signal of pancreatic juice in area with spatially selective inversion recovery pulse (i.e., frequency with which pancreatic juice flowed into pancreatic duct). Frequency of secretion was significantly reduced with aging (r =.74, p <.1) Age (y) Fig. 4 Graph shows relationship between age and secretion grade, based on distance that pancreatic juice moved within pancreatic duct in area with spatially selective inversion recovery pulse (grade, no flow; grade 1, < 5 mm; grade 2, 5 1 mm; grade 3, mm; grade 4, > 15 mm). Secretion grade showed significant decline with aging (r =.77, p <.1). leading to a rigid fixation of the duct, alteration and irregularities of diameter of ducts, presence of intraductal material (mucous or protein plugs), atrophy of pancreatic acinar tissue, and decreased number and size of zymogen granules [4 6]. Also, it may be caused by decreased sensitivity to hormones as well as the decreased blood flow due to arteriosclerosis. Finally, it may be explained by the impaired motility of the sphincter of Oddi due to the reduced contractility and the sclerotic change of the major papilla. The most accurate technique for the assessment of exocrine pancreatic secretion requires duodenal intubation and sampling and analysis of pancreatic juice. However, this direct technique with potential morbidity is time consuming and invasive with poor reproducibility [22]. MRCP during IV administration of secretin has been reported to allow measurement of exocrine pancreatic secretion by monitoring enlargement of the main pancreatic duct and duodenal filling [17, 23, 24]. However, MRCP during secretin administration is not used in everyday practice, but rather selectively, because of its higher cost and the need for dedicated personnel to monitor the examination [18]. Additionally, the secretin product is currently not available in several countries. By contrast, the semiquantitative measurements obtained using cine-dynamic MRCP with spatially selective IR pulse can be easily performed in clinical practice; this technique does not require the injection of any drugs and reflects the physiologic secretion of pancreatic juice. Thus, cine-dynamic MRCP with spatially selective IR pulse may be included in pancreatic MRI examinations as a part of standard clinical protocol and provide functional information associated with age-related change of exocrine pancreatic secretion with minimal cost or effort. Impaired nutrition is common in the elderly. Because exocrine pancreatic secretion plays a central role in food assimilation and maintenance of a normal nutritional status, it would be of great practical interest to know whether pancreatic insufficiency as a result of aging might be a cause of malabsorption in old patients. Thus, cine-dynamic MRCP may provide useful information to assess the impact that age-related changes in the secretory flow of pancreatic juice have in the nutritional alterations that frequently appear in the elderly, although mild pancreatic insufficiency would not affect the digestive capacity. Further promising roles of this cine-dynamic MRCP are expected in clinical practice in the future including the evaluation of exocrine pancreatic function in patients with chronic pancreatitis. In the previous study evaluating exocrine pancreatic function and aging with duodenal suction test, no distinctive features were found that permitted distinguishing exocrine pancreatic function in elderly patients from that in the group with chronic pancreatitis, indicating that elderly subjects had as much exocrine pancreatic dysfunction as did patients with AJR:22, May

5 Downloaded from by on 4/21/18 from IP address Copyright ARRS. For personal use only; all rights reserved chronic pancreatitis [11, 21]. This finding suggested that, in elderly patients (> 7 years old), it would be difficult to differentiate normal aging pattern (the decreased secretion grade and the frequency of secretion) in cine-dynamic MRCP from pathologic findings in chronic pancreatitis. Therefore, it would be important to understand that decreased pancreatic secretion seen in cine-dynamic MRCP in elderly patients does not necessarily indicate the finding caused by chronic pancreatitis. One potential limitation of the current study is that the population was not uniformly distributed with respect to age, thus potentially underweighting the very young and very old. However, our patient population reflects the distribution of people presenting for MRCP examinations. Younger patients were less frequently referred for MRCP examinations, whereas older patients were more likely to be excluded because of the presence of pancreatic diseases. A second limitation is that we did not take patient height, weight, and sex into account, although a previous study showed that these factors did not affect the exocrine pancreatic function [9, 21]. Third, although the patients in the present study did not have pancreatic symptoms, they were not representative of a healthy population because some patients had hepatobiliary disorders. However, it had been reported that no significant exocrine pancreatic dysfunction was found on the basis of fecal elastase 1 concentration in the overall study group of patients with biliary duct pathology, as compared with the control group [25], even though the possibility of the presence of subclinical damage to the pancreas cannot be excluded. Further, another study showed that there was no change in pancreatic secretion due to distention of gallbladder and common bile duct [26]. Fourth, the present study is limited by lack of a reference standard to which the results of cine-dynamic MRCP could be compared; however, there are in fact no other imaging methods available as a reference standard that shows the flow of the pancreatic juice. Finally, a theoretic disadvantage of this technique is the assessment of the secretion grade and frequency estimating fluid output (secretory volume) of pancreatic juice, not peak bicarbonate concentration or pancreatic enzyme (amylase and lipase) output. However, this was not shown to be a problem because there was a good correlation with fluid output and the results of noninvasive measurements of enzymatic activity [11, 27]. Despite these limitations, our study confirmed the capability of cine-dynamic MRCP Torigoe et al. using spatially selective IR pulse to semiquantitatively evaluate age-related changes in the secretory flow of pancreatic juice in the main pancreatic duct. In conclusion, cine-dynamic MRCP using spatially selective IR pulse was able to show age-related change in the secretory flow of pancreatic juice in the main pancreatic duct visually and noninvasively. Notably, aginginduced decrease in exocrine pancreatic secretion may appear in elderly patients without pancreatic diseases. References 1. Bowman BB, Rosenberg IH. Digestive function and aging. Hum Nutr Clin Nutr 1983; 37: Geokas MC, Haverback BJ. The aging gastrointestinal tract. Am J Surg 1969; 117: Hastier P, Buckley MJ, Dumas R, et al. A study of the effect of age on pancreatic duct morphology. Gastrointest Endosc 1998; 48: Kreel L, Sandin B. Changes in pancreatic morphology associated with aging. Gut 1973; 14: Ogiu N, Nakamura Y, Ijiri I, Hiraiwa K, Ogiu T. A statistical analysis of the internal organ weights of normal Japanese people. Health Phys 1997; 72: Detlefsen S, Sipos B, Feyerabend B, Kloppel G. Pancreatic fibrosis associated with age and ductal papillary hyperplasia. Virchows Arch 25; 447: Laugier R, Sarles H. The pancreas. Clin Gastroenterol 1985; 14: Laugier R, Bernard JP, Berthezene P, Dupuy P. Changes in pancreatic exocrine secretion with age: pancreatic exocrine secretion does decrease in the elderly. Digestion 1991; 5: Vellas B, Balas D, Moreau J, et al. Exocrine pancreatic secretion in the elderly. Int J Pancreatol 1988; 3: Kozu T, Suda K, Toki F. Pancreatic development and anatomical variation. Gastrointest Endosc Clin N Am 1995; 5: Ishibashi T. Aging and exocrine pancreatic function evaluated by endoscopic retrograde aspiration of pure pancreatic juice [in Japanese]. Okayama Igakkai Zasshi 1999; 111: Matos C, Metens T, Deviere J, et al. Pancreatic duct: morphologic and functional evaluation with dynamic MR pancreatography after secretin stimulation. Radiology 1997; 23: Heverhagen JT, Muller D, Battmann A, et al. MR hydrometry to assess exocrine function of the pancreas: initial results of noninvasive quantification of secretion. Radiology 21; 218: Nanashima A, Yamaguchi H, Fukuda T, et al. Evaluation of pancreatic secretion after administration of secretin: application of magnetic resonance imaging. J Gastroenterol Hepatol 21; 16: Czakó L, Endes J, Takács T, Boda K, Lonovics J. Evaluation of pancreatic exocrine function by secretin-enhanced magnetic resonance cholangiopancreatography. Pancreas 21; 23: Cappeliez O, Delhaye M, Deviere J, et al. Chronic pancreatitis: evaluation of pancreatic exocrine function with MR pancreatography after secretin stimulation. Radiology 2; 215: Punwani S, Gillams AR, Lees WR. Non-invasive quantification of pancreatic exocrine function using secretin-stimulated MRCP. Eur Radiol 23; 13: Balci NC, Alkaade S, Magas L, Momtahen AJ, Burton FR. Suspected chronic pancreatitis with normal MRCP: findings on MRI in correlation with secretin MRCP. J Magn Reson Imaging 28; 27: Jin EH, Ichikawa T, Erturk SM, Motosugi U, Hirano M, Araki T. Calibrated magnetic resonance hydrometry to quantify pancreatic juice: a preliminary study. J Magn Reson Imaging 29; 29: Ito K, Torigoe T, Tamada T, Yoshida K, Murakami K, Yoshimura M. The secretory flow of pancreatic juice in the main pancreatic duct: visualization by means of MRCP with spatially selective inversionrecovery pulse. Radiology 211; 261: Ishibashi T, Matsumoto S, Harada H, et al. Aging and exocrine pancreatic function evaluated by the recently standardized secretin test. Nippon Ronen Igakkai Zasshi 1991; 28: Siegmund E, Lohr JM, Schuff-Werner P. The diagnostic validity of non-invasive pancreatic function tests: a meta-analysis [in German]. Z Gastroenterol 24; 42: Schneider AR, Hammerstingl R, Heller M, et al. Does secretin-stimulated MRCP predict exocrine pancreatic insufficiency? A comparison with noninvasive exocrine pancreatic function tests. J Clin Gastroenterol 26; 4: Sanyal R, Stevens T, Novak E, Veniero JC. Secretinenhanced MRCP: review of technique and application with proposal for quantification of exocrine function. AJR 212; 198: Wasielica-Berger J, Dlugosz JW, Laszewicz W, et al. Exocrine pancreatic function in biliary tract pathology treated with the endoscopic methods. Adv Med Sci 27; 52: Koller M, Triebling AT, Toth L, Dreiling DA. Enteropancreatic reflexes. Part 5. The effect of gallbladder and common bile duct distention on pancreatic exocrine secretion. Mt Sinai J Med 1986; 53: Gillams A, Pereira S, Webster G, Lees W. Correlation of MRCP quantification (MRCPQ) with conventional non-invasive pancreatic exocrine function tests. Abdom Imaging 28; 33: FOR YOUR INFORMATION The reader s attention is directed to the commentary on this article, which appears on pages AJR:22, May 214

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